579 CHAPTER TWENTY-NINE conversion of pyruvate to acetyl CoA. The pyruvate is derived from glucose, lactate and alanine. Pyruvate also undergoes conversion to oxaloacetate by pyruvate carboxylase, which also feeds into the Krebs cycle. Krebs cycle The primary function is to oxidize acetyl-CoA generated from metabolism of carbohydrates, ketone bodies, fatty acids and amino acids into reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2). These are then respiratory chain (Fig. 29.6). The pyruvate dehydrogenase (PDH) complex regulates the cycle’s activity. Biochemistry Pyruvate dehydrogenase (PDH) complex The complex is formed from three enzymes (E1, E2, E3), and E1 requires the co-factor thiamine diphosphate. The complex provides substrate for the Krebs cycle in the form of acetyl-CoA by facilitating the Fig. 29.5 The Krebs cycle. CoA, coenzyme A; NAD+ , nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; KGDHC, α-ketoglutarate dehydrogenase; Q, coenzyme Q; FAD, flavin adenine dinucleotide; FADH2, reduced flavin adenine dinucleotide. Glucose Alanine Pyruvate Acetyl coenzyme A PDHC KGDHC Succinate Succinyl CoA NAD+ + FAD QH2 Q NADH + H+ + FADH2 NADH + H+ NADH + CO2 + H+ NADH + CO2 + H+ Glutamate Proline NAD+ NAD++ CoA NAD+ Phosphoenolpyruvate Lactate TCA Oxaloacetate Citrate α-ketoglutarate Fig. 29.6 The mitochondrial respiratory chain. NADH, reduced nicotinamide adenine dinucleotide; ATP, adenosine triphosphate; Q, coenzyme Q; C, cytochrome c; , electron flux; , proton flux. Outer membrane Inner membrane H+ H+ H+ H+ Matrix I II III IV V NADH Succinate Oxygen ATP Complex Q C
29 580Metabolic medicine complex system result in disrupted supply of ATP. Those organs with the greatest energy demands are most severely affected, i.e. brain, heart, kidney, retina, skeletal muscle. Presentation Clinical presentation is very varied and while clinical syndromes are recognized (Table 29.10), mitochondrial disease should be considered in the following instances: • Multi-system disease • Elevated lactate, though differential is wide and raised lactate is not a compulsory requirement (see Acid–base disturbance, above) • Leigh syndrome with its characteristic cranial magnetic resonance imaging findings of symmetrical changes of the basal ganglia and the brainstem. Diagnosis and management Investigation is difficult (see Investigations used in screening and diagnosis, below) and often only symptomatic treatment is possible, e.g. seizure management, gastrostomy feeding. Thiamine has been used in patients with PDH deficiency in order to increase the efficiency of the reactions undertaken by E1. Effects have been variable. The use of a ketogenic diet (see Principles of dietary treatment, below) in patients with PDH deficiency has been marginally more successful, as it serves to provide an alternative source of acetyl-CoA for use by the Krebs cycle. utilized in oxidative phosphorylation. The cycle also provides intermediates for other pathways and has links with gluconeogenesis, lipogenesis and amino acid metabolism. Mitochondrial respiratory chain The mitochondrial respiratory chain (MRC), also known as the electron transport chain, is present in all mitochondria-containing cells. The chain is composed of five complexes (I to V) and two link molecules (ubiquinone and cytochrome c) embedded within the mitochondrial membrane (see Fig. 29.6). It is the site of ATP production. This occurs though two coupled processes: 1. Electron transport: Complexes I–IV comprise a series of redox reactions utilizing NADH and FADH2 from the Krebs cycle. Ubiquinone shuttles electrons form complexes I and II to III. Cytochrome c shuttles electrons from complex III to IV. This flow of electrons is used to pump protons across the inner mitochondrial membrane to the intermembrane space, so creating a proton (H+ ) gradient. 2. Oxidative phosphorylation: Complex V (ATP synthase) channels the protons back into the mitochondrial matrix with the generation of ATP. Clinical Strictly speaking, mitochondrial disorders are those directly resulting from deficits in energy production by oxidative phosphorylation. Disturbances of this Table 29.10 Common mitochondrial disorders Syndrome Clinical features Onset (years) Common mutations MERRF Myoclonic epilepsy with ragged red fibres 5–15 m.8344G>A NARP Neuropathy, ataxia, retinitis pigmentosa 5–30 m.8993T.G/C Barth Cardiomyopathy, cyclical neutropenia, myopathy, short stature Neonate or infancy TAZ gene Ethylmalonic encephalopathy Developmental delay, acrocyanosis, petechiae, diarrhoea Neonatal or infancy ETHE1 gene GRACILE Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death Neonatal or infancy BCS1L gene MELAS Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes. Myopathy, migraine, vomiting, seizures, visual and hearing disturbance 5–15 80% m.3243A>G Alpers Intractable seizures and liver involvement Early childhood POLG Kearns–Sayre Triad: onset <20 years, progressive external ophthalmoplegia, pigmentary retinopathy plus at least 1 of cardiac conduction block, cerebellar ataxia, CSF protein >0/1 g/L <20 90% due to large mtDNA deletions +/− duplications
581 CHAPTER TWENTY-NINE mitochondrial matrix via the carnitine:acylcarnitine translocase transporter. Once in the matrix, CPT II converts the fatty acylcarnitine back to a fatty acyl-CoA and carnitine, the latter exported back into the cytosol. • β-Oxidation occurs via a spiral pathway. Each turn shortens the acyl-CoA by two carbons. There are four cycles; each catalysed by a carbon chain length specific enzyme: – Acyl-CoA dehydrogenase (irreversible) – Long-chain acyl-CoA dehydrogenase (C14–20) – Medium-chain acyl-CoA dehydrogenase (C8–12) – Short-chain acyl-CoA dehydrogenase (C4–6) • The net effect is production of: – Electrons, which are transferred to the respiratory chain – Acetyl-CoA, which is either oxidized in the Krebs cycle or used by the liver to create ketone bodies. Clinical Presentation Fatty acid oxidation disorders have three classic presentations: 1. Hypoketotic hypoglycaemia. If left untreated, encephalopathy ensues, often accompanied by liver dysfunction and hepatomegaly, leading eventually to coma and death. Fatty acid metabolism and ketone synthesis Fat is an important stored energy source, especially at times of fasting, when fatty acid oxidation provides up to 80% of cellular energy. Fatty acids are used preferentially by the heart and by muscles during sustained exercise. The brain is unable to directly metabolize fatty acids but can use ketone bodies generated during fatty acid oxidation. β-Hydroxybutyrate and acetoacetate are the principal ketone bodies. They are generated from acetyl-CoA by β-oxidation of fatty acids. Their conversion to acetyl-CoA allows their use as an alternative fuel. Disorders of ketogenesis resemble that of fatty acid oxidation disorders; in contrast to defects of ketolysis, where severe ketosis predominates. Biochemistry Fatty acid metabolism has three stages (Fig. 29.7): • Entry of fatty acids into mitochondria. Fatty acids are mobilized by lipase. Medium- and short-chain fatty acids permeate the mitochondrial membrane and are activated to CoA esters in the matrix in preparation for β-oxidation. Long-chain fatty acids (those with 16–20 carbon atoms) must be activated to coenzyme A esters in the cytoplasm. They join with carnitine to form a fatty acylcarnitine via CPT 1 (carnitine palmitoyltransferase I) and transferred into the Fig. 29.7 Fatty acid oxidation. CPT 1, carnitine palmitoyltransferase I; CPT II, carnitine palmitoyltransferase II; carnitine acylcarnitine translocase (CACT). Long chain fatty acids Medium chain fatty acids Carnitine Fatty acylcarnitine CPTI Mitochondrial membrane CACT CPTII Fatty acyl-CoA Ketone bodies Acetyl-CoA B-oxidation Dicarboxylic acids Carnitine Fatty acylcarnitine CACT
29 582Metabolic medicine Vitamin-responsive disorders Vitamins act as co-factors and co-enzymes in many biochemical systems. Consequently, there are a number of vitamin-responsive disorders (Table 29.12). The following case history highlights the role of active and inactive co-factors. 2. Cardiomyopathy, arrhythmias or conduction defects. 3. Myopathy or acute rhabdomyolysis. Diagnosis Diagnosis is based upon clinical presentation and measurement of carnitine and acylcarnitine levels and urine organic acids (Table 29.11). The majority of episodes are triggered by intercurrent illness or fasting. Management is therefore avoidance of fasting and reduction of catabolic stress at times of intercurrent illness by use of an emergency regimen (see Principles of dietary treatment, below). Those with carnitine transporter defect require carnitine. Table 29.11 Summary of disorders of fatty acid metabolism Disorder Presentation Diagnosis Carnitine/acylcarnitine Urine organic acid CTD Cardiomyopathy, muscle weakness, liver disease Asymptomatic ↓↓↓ free/total carnitine No dicarboxylic aciduria CPT I Liver disease, renal tubular acidosis N–↑ total/free carnitine ↓C16, C18, C18:1 No dicarboxylic aciduria CPT II Early onset: cardiomyopathy, liver disease Attenuated: exercise intolerance, rhabdomyolysis ↓ total carnitine ↑ ratio C16 + C18:1/C2 No or non-specific dicarboxylic aciduria CACT Severe cardiomyopathy, arrhythmias, liver disease ↓↓ total carnitine ↓ free carnitine ↑ C16, C18, C18:1 May have dicarboxylic aciduria VLCAD Severe: cardiomyopathy, liver disease, hepatomegaly, sudden death in infancy Attenuated: late-onset rhabdomyolysis, exercise intolerance ↑ C14:1 and ratio C14:1/C12:1 C6–C14 dicarboxylic aciduria LCHAD Cardiomyopathy, liver disease, hypotonia, neuropathy, retinopathy; late-onset rhabdomyolysis Mother with affected fetus may have steatosis or HELLP syndrome in pregnancy ↑ lactate and hydroxylcompounds C14-OH, C16-OH, C18:1–OH C6–C14 dicarboxylic acids MCAD Reye-like rapidly progressive crisis after 8–16 hours fasting, during ordinary illness or after surgery Now identified by newborn screening (see Investigations used in screening and diagnosis, below) ↑ C8, C6, ratio C8:C10 C6–C14 dicarboxylic aciduria, suberylglycine, hexanoylglycine. CACT, carnitine translocase deficiency; CPT I/II, carnitine palmitoyltransferase I/II deficiency; CTD, carnitine transporter defect; LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; MCAD, medium-chain acyl-CoA dehydrogenase deficiency; VLCAD, very-long-chain acyl-CoA dehydrogenase deficiency. Case history Early neonatal death Term baby observed on postnatal ward for 24 hours in view of prolonged rupture of membranes. Discharged home on day 2, breastfeeding. On day 3 he became apnoeic and required resuscitation and transfer to paediatric intensive care. He was encephalopathic and a CT head was consistent with hypoxic–ischaemic encephalopathy. Care was withdrawn. Cause of death was presumed to be sepsis; however, post-mortem acylcarnitine and urine organic acid analysis were consistent with MCAD deficiency. Mutation analysis confirmed Case history Metabolic epileptic encephalopathy A newborn, term male baby born after a normal pregnancy and delivery presents with seizures on day 1 of life, which become intractable despite standard anti-convulsant therapy. The possibility of pyridoxine-responsive seizures is raised. Pyridoxine is given intravenously at 100 mg/kg with no effect. Pyridoxal phosphate is given orally baby was homozygous for the common mutation c.985A>G. Key points: • MCAD deficiency can present in the first few days of life before screening results are available • If there are older siblings, they should be tested if they were born prior to newborn screening • Future pregnancies should be managed prospectively in accordance with national guidelines (see www.bimdg.org.uk)
583 CHAPTER TWENTY-NINE Mitochondrial genetics Mitochondrial genome (mtDNA) is inherited exclusively from the mother as, after fertilization of the ovum, the sperm-derived mitochondria disappear in early embryogenesis. In any one cell there are hundreds of copies of mtDNA because there are many copies in each mitochondrion and many mitochondria per cell. An mtDNA mutation may affect all (homoplasmy) or a proportion (heteroplasmy) of copies of the mtDNA in a cell. Clinical disease only occurs once a threshold of heteroplasmy is exceeded. The threshold is dependent upon the severity of the mutation and the susceptibility of the tissue to the effects of the mutation. Above this threshold, the severity of the clinical phenotype will depend upon the level of heteroplasmy. For example, m.3243A>G causes MELAS syndrome in people with high levels of the mutation, but those with lower levels may only suffer diabetes mellitus and deafness. The level of heteroplasmy and hence phenotype can vary from mother to child (see Chapter 9, Genetics, for further details). Newborn screening This is offered to all newborn babies on day 5–7 of life (see Chapter 11, Neonatal medicine). The conditions tested for are cystic fibrosis, congenital hypothyroidism, haemoglobinopathies, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, phenylketonuria (PKU), maple syrup urine disease (MSUD), isovaleric aciduria (IVA), glutaric aciduria type I (GA1) and homocystinuria (HCU). The last six are inborn errors of metabolism. MCAD deficiency MCAD deficiency is a disorder of fatty acid oxidation (see Fatty acid metabolism and ketone synthesis, above). It has an incidence in the UK of approximately 1 in 10,000 births. It is detected on newborn screening by measuring the octanoylcarnitine (C8) level. If elevated, the test is repeated. Screen positive patients are referred to the nearest specialist metabolic centre for confirmation with repeat acylcarnitine testing, mutation analysis and urine organic acid analysis looking for dicarboxylic aciduria. Management is with the avoidance of fasting and the use of an emergency regimen at times of illness to prevent metabolic decompensation (see Principles of dietary treatment, below). Phenylketonuria Phenylketonuria (PKU) is an aminoacidopathy due to a deficiency of phenylalanine hydroxylase, which Genetics of metabolic disorders The full spectrum of inheritance modes are seen in IEM (Table 29.13). The most common pattern is autosomal recessive. While consanguineous parentage increases the risk of IEM, it is not obligatory. Table 29.12 Vitamin responsive disorders Vitamin Used in B1 (thiamine) Thiamine-responsive variants of maple syrup urine disease, PDH def, complex I def B2 (riboflavin) Glutaric aciduria type II, complex I B6 (pyridoxine) Pyridoxine-responsive homocystinuria, pyridoxine-dependent seizures B6 (pyridoxal phosphate) Pyridoxamine-5-phosphate oxidase def B7 (biotin) Biotinidase def, multiple carboxylase def, biotin responsive basal ganglia disease B9 (folic acid) Methylenetetrahydrofolate reductase (MTHFR) def B12 (hydroxycobalamin) B12-responsive MMA (methylmalonic acidaemia), MTHFR def Vitamin E Abetalipoproteinaemia, glutathione synthase def def, deficiency; PDH, pyruvate dehydrogenase. Table 29.13 Modes of inheritance Inheritance mode Examples Autosomal recessive Organic acidaemias, UCD (except OTC), MPS (except type II), aminoacidopathies, glycogen storage disorders Autosomal dominant GLUT1, familial hypercholesterolaemia X-linked OTC deficiency, Barth syndrome, MPS type II, creatine transporter deficiency, Lesch–Nyhan Maternal MELAS, Leber’s hereditary optic atrophy, Pearson syndrome, MERRF, NARP, MIDD GLUT1, glucose transporter 1; MELAS, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibres; MIDD, maternally-inherited diabetes and deafness; MPS, mucopolysaccharidosis; NARP, neuropathy, ataxia, retinitis pigmentosa; OTC, ornithine transcarbamylase; UCD, urea cycle disorder. with immediate effect. Investigations confirm pyridoxal phosphate deficiency with a mutation found in the PNPO gene. Key points: • Pyridoxine must be given in controlled circumstances as it can cause apnoea • If pyridoxine is ineffective, a trial of the biologically active pyridoxal phosphate should be given. Only available as an oral preparation.
29 584Metabolic medicine Often the diagnosis is unclear, with many children presenting with chronic, non-specific signs such as developmental delay (DD), faltering growth, dysmorphism or seizures. Even those presenting acutely with metabolic acidosis or hyperammonaemia will need multiple investigations to elucidate the aetiology. Investigations are often staged (Tables 29.15–29.16), except in the moribund child, when efforts must be made to obtain samples peri-mortem to minimize post-mortem artefact. Routine pathology samples should be sent concurrently, i.e. full blood count, urea and electrolytes, coagulation, as many of these profiles are deranged in metabolic disease. Discussion with a specialist centre is vital to guide the process. converts phenylalanine to tyrosine. Accumulation of phenylalanine, if untreated, causes microcephaly, seizures and learning difficulties. Newborn screening aims to detect a raised phenylalanine (Phe) level. If the level is increased, the test is repeated and the tyrosine level is measured. Screen positive patients are referred to the local metabolic service for confirmation with repeat testing. If the phenylalanine level is markedly raised and the tyrosine level is low, PKU is confirmed. However, 1% of patients with raised Phe levels will not have PKU but will have a disorder of pterin metabolism. This group of disorders leads to disturbances in central nervous system amines and results in a neurological phenotype, requiring treatment with L-dopa, tetrahydrobiopterin and/or 5-hydroxytryptophan. All PKU-positive patients are therefore tested for pterin defects when reviewed by the specialist centre. PKU is treated with a low protein diet, so restricting intake of phenylalanine in conjunction with a phenylalanine-free amino acid supplement. The latter is vital to ensure nutritional requirements for all nonessential and essential amino acids (Table 29.14) are met to allow optimal growth. The amount of natural protein allowed is calculated using an exchange system whereby one food can be exchanged for another of equivalent phenylalanine content. The number of allowed exchanges is variable and depends upon blood phenylalanine level, severity of enzyme deficiency, energy intake, compliance with protein substitute and age and weight of the child. Phe levels are monitored by the patients sending in regular blood spots for analysis and altering the diet according to the level in relation to target range. Investigation of suspected metabolic disease If a diagnosis is clear, then specific diagnostic investigations can be performed, including genetic testing. Table 29.14 The amino acids Essential Non-essential Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Alanine Arginine Asparagine Aspartate Cysteine Glutamate Glutamine Glycine Proline Serine Tyrosine Table 29.15 Typical first-line investigations (guided by clinical picture) Sample Test Indication Blood Amino acids and acylcarnitines Possible UCD, organic acidaemia or aminoacidopathy, DD, seizures, faltering growth, dysmorphism Beutler test Galactosaemia Very-long-chain fatty acids Possible peroxisomal disorder White cell enzymes Dysmorphism, organomegaly, learning difficulties, developmental regression Lactate Mitochondrial disease, GSDs Urine Organic acids Possible organic acidaemia, FAOD Amino acids Tubulopathy, cystinosis MPS and oligosaccharides MPS disorder or oligosaccharidosis DD, developmental delay; FAOD, fatty acid oxidation disorder; GSDs, glycogen storage disorders; MPS, mucopolysaccharidosis; UCD, urea cycle disorder. Table 29.16 Second-line investigations (guided by clinical picture) Sample Test Indication Cerebral spinal fluid Neurotransmitters Amino acids, glucose and lactate (paired with plasma samples) Neurotransmitter disorders, GLUT1 deficiency, non-ketotic hyperglycinaemia Skin biopsy Fibroblast culture PDH deficiency, flux studies, filipin staining Muscle biopsy Histochemistry and respiratory chain enzymes Mitochondrial disease Liver biopsy Histochemistry and mitochondrial studies GSD, mitochondrial disease GSD, glycogen storage disorder; PDH, pyruvate dehydrogenase.
585 CHAPTER TWENTY-NINE Enzyme replacement therapy Lysosomes can be thought of as the ‘recycling centres’ of our cells. They contain a large number of enzymes required for the intracellular breakdown of various molecules. A deficiency of one of these enzymes leads to a specific lysosomal storage disorder (LSD) (Table 29.18). They are termed ‘storage disorders’ because the loss of the enzyme results in the accumulation (or storage) of the incompletely metabolized substance within the lysosome. This leads to swelling of the lysosome and cellular dysfunction. Clinically, this manifests with the typical features of storage, such as organomegaly and dysmorphism. Some LSDs predominantly affect the central nervous system and are primarily neurological diseases, e.g. Krabbe disease. Lysosomal enzymes are synthesized via the endoplasmic reticulum. They are then processed in the Golgi apparatus, where a mannose-6-phosphate residue is added. The latter identifies it as a lysosomal enzyme. The lysosome ‘picks up’ the enzyme via its mannose-6-phosphate receptor and transports the enzyme inside. Enzyme replacement therapies (ERTs) have been developed for some of the LSDs which exploit this natural process (Table 29.19). In summary, in ERT a recombinant enzyme is produced with a mannose-6-phosphate residue added to it; thus, allowing the manufactured deficient enzyme to be imported into the lysosome. Principles of dietary treatment Many inborn errors of metabolism are treated by dietary modification (Table 29.20). Specialist dietetic advice is essential to ensure nutritional requirements are met. There are four key dietetic strategies, as detailed below. Supplying a deficient product An example would be the need for a regular supply of glucose in a hepatic GSD, such as type I. Children with GSD-I are unable to metabolize glycogen or utilize glucose from gluconeogenesis due to a deficiency of glucose-6-phosphatase (see Glucose and glycogen metabolism, above). They are at risk of hypoglycaemia Mitochondrial disease testing This is notoriously difficult and often no diagnosis is reached, though recent technological advances have improved diagnostic rates. A general guide to investigation: • If there is a characteristic clinical syndrome, proceed straight to testing for the common mutation. • If there is no characteristic clinical syndrome, proceed to muscle biopsy for histochemistry and respiratory chain biochemical analysis and progress to molecular genetics. Principles of pharmacological treatment Many conditions are managed using symptomatic therapies, e.g. anti-convulsants. Table 29.17 summarizes the main medications used in metabolic disease. Table 29.17 Medications used in inborn errors of metabolism Medication Indication Mode of action Arginine Urea cycle disorders Replenishes arginine. Substrate for nitrous oxide. Carglumic acid Hyperammonaemia due to NAGS or CPS deficiency Artificial activator of CPS1 thereby promoting the urea cycle. Carnitine Organic acidaemias, carnitine transporter defects Replenishes body stores. Removes toxic acyl-CoA intermediates from within the mitochondria. Citrulline CPS and OTC deficiency Replenishes citrulline and arginine. Sodium benzoate Hyperammonaemia Conjugates with glycine to form hippuric acid, which is excreted in the urine. Sodium phenylbutyrate Hyperammonaemia Conjugates with glutamine to form phenylglutamine, which is excreted in the urine. CPS, carbamoyl phosphate synthetase; NAGS, N-acetylglutamate synthetase; OTC, ornithine transcarbamylase. Table 29.18 Classification of lysosomal storage disorders Group Deficient breakdown of: Disorders Mucopolysaccharidoses (MPS) Glycosaminoglycans MPS I, II, III, IV, VI, VII Oligosaccharidoses Carbohydrate side-chains from glycoproteins Fucosidosis, α and β mannosidosis Sphingolipidoses Ceramide-containing membrane lipids Gangliosidosis 1 and 2, Niemann–Pick disease A and B, Gaucher types 1, 2 and 3, Fabry, Krabbe
29 586Metabolic medicine The urea cycle disorders, organic acidaemis and other amino acidopathies, such as tyrosinaemia, require dietary protein restriction. It is crucial that, despite the restriction, the diet provides sufficient protein and essential amino acids to meet the safe levels of protein intake specified by the World Health Organization. To achieve this, many patients will require protein substitutes and vitamin/mineral supplementation. Supplying adequate energy and preventing catabolism At times of illness metabolic demands are increased. If these demands are not met, the body enters a state of catabolism. This is also seen during starvation. Certain groups of patients are at risk of metabolic decompensation: • Fatty acid oxidation disorder: at risk of hypoglycaemia • Hepatic GSD: at risk of hypoglycaemia • Urea cycle disorders: at risk of hyperammonaemia • Organic acidaemias: at risk of metabolic acidosis and hyperammonaemia To prevent such a situation arising, patients are provided with an emergency regimen. This involves stopping the normal diet and providing a supply of glucose orally or intravenously with the aim of increasing insulin secretion and reducing catabolism. Oral glucose is preferred during minor illness as it can be given at home. The common glucose polymers used are Caloreen®, Polycose®, Maxijul®, Polycal®, Vitajoule®. The concentration and volume are adjusted according to the patient’s age. The drinks are continued every two hours during the day and three hourly overnight until the child is on the road to recovery. Patients who vomit or refuse to take their emergency regimen, or who deteriorate despite taking it, require hospital admission for intravenous glucose with the aim to supply 6–12 mg/kg/minute of glucose, depending on age. The fluid used should generally be 10% glucose and 0.45% saline with electrolytes added as determined by the plasma electrolytes. If patients become hyperglycaemic, an insulin infusion should be started with appropriate monitoring rather than reducing the concentration of the glucose infusion as it promotes anabolism. Ketogenic diet The brain relies on glucose to provide its energy. GLUT1 is a glucose transporter responsible for facilitating the transport of glucose across the blood– brain barrier. Defects in this system result in low cerebral spinal fluid (CSF) glucose levels with resultant even when well. Management involves the supply of glucose delivered by regular feeds over the day and a continuous feed overnight. The length of time between feeds varies between patients, with some requiring daytime feeds as often as every 11 2 hours. In older patients and those with less severe disease, uncooked cornstarch can be used as a slow release glucose substrate. This reduces the number of feeds during the day and may allow cessation of overnight feeding. Preventing accumulation of a toxic substrate by restricting intake This has already been exemplified in the case of PKU (see Neonatal screening, above). Another example is that of galactosaemia (see Chapter 21, Hepatology) which is due to a deficiency of galactose-1-phosphate uridyltransferase. This is required for the metabolism of the monosaccharide galactose. Presentation is classically in the neonatal period with prolonged jaundice, liver dysfunction, cataracts and sepsis (typically E. coli). The patient is treated with a minimal-galactose diet and due to the extremely limited dairy intake, many require calcium supplementation. Despite strict dietary adherence, outcomes remain sub-optimal due to the endogenous production of galactose in the gastrointestinal tract. Long-term complications include ovarian dysfunction (in females) and learning difficulties. Table 29.19 Lysosomal storage disorders and their available enzyme replacement therapies Disorder Licensed enzyme replacement therapy Gaucher disease types 1 and 3 Fabry disease Mucopolysaccharidosis type I Mucopolysaccharidosis type II Mucopolysaccharidosis type VI Pompe disease Imiglucerase, velaglucerase, taliglucerase Agalsidase alfa, agalsidase beta Laronidase Idursulfase Galsulfase Alglucosidase alfa Table 29.20 Inborn errors of metabolism treated with a specialist diet Disorder Conditions treated with diet Amino acid metabolism Phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinaemia, lysinuric protein intolerance Organic acid metabolism MMA (methylmalonic acidaemia), propionic acidaemia, isovaleric acidaemia, glutaric aciduria type I Carbohydrate metabolism Galactosaemia, hereditary fructose intolerance, glycogen storage disease I
587 CHAPTER TWENTY-NINE Summary Individually, inborn errors of metabolism are rare but, collectively, they are not uncommon. They have a multitude of presentations and, unless thought about, will be missed, as standard investigation of the unwell child will not detect them. Diagnosis is important not just for management of the affected child but also to allow family genetic counselling, as all are inherited conditions. Investigation is central to diagnosis and can be difficult. Management is multi-disciplinary and early discussion with a specialist metabolic centre is vital. A solid understanding of their pathophysiology is essential to understanding these complex disorders. Further reading British Inherited Metabolic Diseases Group. <www.bimdg.org.uk>; [accessed 02.09.15]. Clarke J. A clinical guide to inherited metabolic disease. 3rd ed. Cambridge: Cambridge University Press; 2010. National screening programme information. <http://www.gov. uk/topic/population-screening-programmes>; [accessed 21.12.15]. OMIM (Online Mendelian Inheritance in Man). A compendium of human genes and genetic phenotypes. Available at: <http://www.ncbi.nlm.nih.gov/omim>; [accessed 16.01.16]. Orphanet. Portal for rare diseases and orphan drugs. Available at: <http://www.orpha.net>; [accessed 16.01.16]. neurological disease. Patients classically present with an early-onset epileptic encephalopathy resistant to standard anti-convulsant medications. Unrecognized, the patient suffers developmental delay and evolution of a movement disorder. Non-classical forms have a varied phenotype but remain neurological in nature. Diagnosis is based on a low plasma to CSF glucose ratio of <0.5 with normal CSF cell count, protein and lactate. Confirmation is with mutation analysis. Treatment is with a ketogenic diet, as the brain is able to use ketones as an alternative energy source (see Fatty acid metabolism and ketone synthesis, above). While the diet can alleviate some of the neurological problems, patients often have residual cognitive problems. The classical ketogenic diet is based on four grams of fat being consumed for every one gram of protein and carbohydrate. Side effects include constipation, mild hyperlipidaemia, platelet dysfunction and, very rarely, kidney stones or pancreatitis. The mediumchain triglyceride (MCT)-based diet is an alternative to the classical diet. MCT provides 60% of the energy with saturated fat, with carbohydrate and protein providing the remaining 40%. If patients on the diet become unwell, they must not be given dextrosecontaining solutions (unless hypoglycaemic) as this shuts off ketosis and can cause recurrence of seizures.
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LEARNING OBJECTIVES By the end of this chapter the reader should: • Know and understand the anatomy and embryology of the eye • Understand how the structure of the eye relates to function • Understand the normal development of vision and the pathophysiology of visual impairment • Know the physiology of the eye and its movement • Know the genetic and environmental factors in the aetiology of eye disorders • Recognize congenital eye disease, enabling early prevention and treatment of blinding conditions • Understand the action of pharmaceuticals used in eye disease and know which systemic drugs can cause ocular toxicity • Know when an ophthalmic phenotype can help to make a systemic/genetic diagnosis • Know when a systemic disease puts a child at risk of ophthalmic disease 589 CHAPTER THIRTY Although ophthalmology may seem a fairly minor topic to the generalist, paediatric eye and visual disorders are common in both primary and secondary care settings. The eyes, their visual pathways and higher visual processing mature throughout early childhood. Good visual function depends on all these factors. These stages of normal visual development and the way we assess them are covered in Chapter 4, Normal child development. Epidemiology of childhood visual impairment Visual impairment in childhood impacts all areas of a child’s development and influences their future prospects. In the UK, nearly 4% of the childhood population are registered severely visually impaired or blind (compared to 12% in developing countries) and half these children will have additional motor, sensory, learning impairments or systemic disease. Our screening programmes and access to specialist paediatric ophthalmic care prevent many cases of severe visual impairment, and the majority (75%) of children registered blind in the UK have an unpreventable and untreatable cause. The registration process facilitates the educational and social support these children need. The level of visual impairment is based on corrected binocular visual acuity (using a Snellen chart) and visual fields. The definitions of sight impairment are shown in Box 30.1. Applied embryology of the eye The developing eye The eye develops from a complex, coordinated interaction between surface ectoderm, neuroectoderm and the mesenchyme (comprising mesoderm and neural crest cells), mediated by many developmental genes (Fig. 30.1). The optic fissure closes in the sixth week of gestation and, by the beginning of the second trimester, the rudimentary eye has developed, although subsequent differentiation and maturation occur beyond term. Louise Allen Ophthalmology C H A P T E R 30
30 590Ophthalmology where no globe is present (incidence 2/100,000 live births). In microphthalmos, a small globe, which may or may not have visual potential, is present (incidence 19/100,000 live births). An absent or very small globe will fail to stimulate orbital growth; orbital expanders and conformers should be fitted within weeks of birth in order to prevent permanent orbital asymmetry. Ocular coloboma is a more common malformation (incidence 1/20,000 live births), resulting from failure of closure of the optic fissure in the sixth gestational week. This is often an isolated anomaly but may also characterize a syndrome (e.g. CHARGE: Coloboma, Heart abnormalities, Atresia choanae, Retardation of Growth and development and Ear/hearing abnormalities). The coloboma can affect the inferonasal iris (Fig. 30.2A), and/or the inferior choroid and retina and the optic nerve, the latter two resulting in visual impairment (Fig. 30.2B). Aniridia Although the name suggests otherwise, this is a malformation of the whole eye, usually causing partial or total absence of the iris, cataract, corneal stem cell Abnormal ocular development Anophthalmos, microphthalmos and coloboma This is a spectrum of early ocular malformation and may be unilateral or of varying severity in each eye. The most severe manifestation is anophthalmos, Fig. 30.1 Stages of eye development and some of the genes that control it. Forebrain Optic sulci Midbrain Optic vesicle Cross section Ectoderm (blue) Neuroectoderm (green) Mesenchyme (yellow) Week 3: The first step in eye development is the development of the optic sulci. Genes: PAX6, PAX2, SOX2, SOX3, FOXE2 Week 4: Cross-section through forebrain (red dashed line). The invaginating lens placode comprised of surface ectoderm forms the optic vesicle. The neuro-ectoderm lines the vesicle. Lens Hyaloid artery Optic fissure Week 7: The neuro-ectoderm forms the retina and optic nerve. The surrounding mesenchyme forms the hyaloid vasculature, vitreous and inner layers of the cornea. Extra-ocular muscles begin to form. Genes: PITX2, FOXC1, CYP1B1 Week 6: Cross section through optic vesicle. The lens placode (ectodermal thickening) begins to separate from the surface forming the lens. The inferiorly located optic fissure is starting to close. Box 30.1 Definitions of sight impairment Severely sight impaired (SVI)/blind: • Less than 3/60 (the top letter can only be read at 3 metres) with a full visual field • From 3/60–6/60 accompanied by severe visual field restriction • Better than 6/60 but a visual field restricted to 10 degrees or less Sight impaired/partially sighted: • From 3/60–6/60 with full visual fields • Up to 6/24 with a moderate visual field defect • 6/18 or better with a gross visual field defect, e.g. homonymous hemianopia
591 CHAPTER THIRTY demonstrated by visual evoked potentials). X-linked ocular albinism causes the ocular features of albinism without significant cutaneous involvement. Vitreo-retinal dysplasia This is thought to be caused by abnormal retinal vasculogenesis. At its most severe, the retina is an unrecognizable funnel of neurovascular tissue projecting from the optic disc into the vitreous cavity at birth. In less severe cases, there are localized areas of retinal non-perfusion and ischaemia; early recognition and laser treatment to these areas can prevent neovascularization and subsequent retinal detachment. Babies with incontinentia pigmenti (IKBKG gene mutation, X-linked dominant, lethal in males) are at risk of developing abnormal retinal vasculature and require regular retinal examination from birth in order to prevent retinal detachment with laser treatment. Optic nerve hypoplasia Optic nerve hypoplasia causes a small optic nerve head on fundoscopy, often associated with tortuous retinal veins and a variable level of visual impairment. Maternal risk factors include young age, maternal diabetes and a history of excessive alcohol or use of illicit drugs during pregnancy. There are many systemic associations of optic nerve hypoplasia, including fetal alcohol syndrome and Dandy–Walker syndrome. More commonly, optic nerve hypoplasia is associated with endocrine abnormalities due to panhypopituitarism (may present as neonatal jaundice, hypoglycaemia and seizures) or specific mid-line CNS malformations, such as septo-optic dysplasia, characterized by absence of the septum pellucidum and thinning or agenesis of the corpus callosum. Applied anatomy of the eye The developed eye (Fig. 30.3) The axial length of the eye at birth is around 17 mm. The globe grows particularly rapidly in the first six months, reaching the adult axial length of 22 mm by 5 years. The volume of the neonatal eye is approximately 2.8cm3 compared to the adult volume of 7cm3 . Orbital volume doubles in the first year of life and is dependent on the presence of the globe. The eye is described as having an anterior segment (including conjunctiva, episclera and the externally visible portion of sclera, cornea, anterior chamber, iris and lens) and a posterior segment (including vitreous cavity, retina, retinal pigment epithelium and choroid and posterior sclera). The ophthalmic artery (a branch of the internal carotid artery) supplies the eyelids and orbit. The central retinal artery branches off the Fig. 30.2 A. Iris coloboma causes a defect in the inferonasal iris. B. A chorioretinal coloboma affects the inferonasal fundus; severe forms can cause deep excavation of the optic disc and macula, severely impairing vision and causing leukocoria (white reflex on direct ophthalmoscopy). A B failure and absence of the fovea (foveal hypoplasia), which causes poor vision and nystagmus. Most cases are autosomal dominant (due to inherited point mutations in PAX6). However, in sporadic aniridia, a novel micro-deletion can involve PAX6 and a neighbouring tumour suppressor gene causing WAGR syndrome (Wilm tumour, Aniridia, Genito-urinary abnormalities and Retardation): newborns with sporadic aniridia require urgent investigation for renal tumours. Albinism Melanin has several important functions in the developing eye. It mediates the complex organization of the fovea and guides the axons of the retinal ganglion cells distally through the optic chiasm. Children born with the more severe forms of autosomal recessive oculocutaneous albinism will have translucent irides, foveal hypoplasia and abnormal axonal decussation at the optic chiasm (a useful diagnostic feature
30 592Ophthalmology Fig. 30.3 Anatomy of the developed eye. Pupil Cornea Iris Suspensory ligament of lens Ciliary body Lens Fovea centralis Anterior chamber Anterior Posterior Posterior chamber Canal of Schlemm Conjunctiva Optic disc Iridocorneal angle Ora serrata Rectus tendon insertion Vitreous body Retina Choroid Sclera Dura mater Subarachnoid space Optic nerve surrounded with pia mater Central artery of retina Lamina cribrosa ophthalmic artery to enter the eye via the optic nerve head, supplying the inner layers of the retina (and, in the fetus, the lens via the hyaloid artery system). The posterior ciliary arteries, derived from the ophthalmic artery, anastomose within the choroid to supply the retinal pigment epithelium and outer layer of the retina, including the photoreceptors. A blood–ocular barrier exists to protect the eye from toxic substances: the blood–retina barrier is maintained by the tight junctions in the retinal capillary bed and between retinal pigment epithelial cells, and the blood– aqueous barrier by the tight junctions of the ciliary epithelial cells. Inflammation, as seen in uveitis, breaks down the blood–ocular barrier, allowing inflammatory cells and proteins to enter the aqueous and vitreous from the circulation. The eye is also immunologically isolated (privileged): if antigens from the eye enter the systemic circulation, for example following penetrating eye injury, this can result in an autoimmune attack on the other eye – a devastating, potentially blinding condition called sympathetic uveitis. Sensation from the orbit is conveyed via the ophthalmic division of the trigeminal nerve. Neuronal connections exist between the trigeminal nucleus and the parasympathetic dorsal nucleus of the vagus nerve. Pressure on the eye(s) during retinopathy of prematurity screening or the traction on the muscles during squint surgery can result in bradycardia and respiratory depression. Immediate cessation of the stimulus combined with administration of an antimuscarinic agent, such as atropine, can reverse the effect. Motor innervation of the orbit is discussed later in this chapter. The structure of the retina The retina is a complex, multi-layered neural structure lining the posterior segment of the globe. It is continuous with the optic nerve posteriorly and fuses anteriorly with the epithelium of the ciliary body at the ora serrata. The retina and retinal pigment epithelium (RPE) are derived from two neuroectodermal layers separated by a potential space. A retinal detachment occurs when fluid enters this space, peeling the retina from the underlying RPE. The retina itself is made up of many layers of neural cells: the outermost layer of the retina is made up of the photoreceptors, rods and cones, which receive metabolic and nutritional support from the underlying RPE and choroid. Central and colour vision is provided by the macular retina, the centre of which is called the fovea. Rods are sensitive to low levels of light and are most numerous in the retinal periphery, giving peripheral and night vision. Cones are classified according to the sensitivity of their photo-pigment: long (red), medium (green) and short (blue) wavelengths. The fovea is responsible for visual acuity; cell bodies and axons of the inner retina are displaced peripherally at the fovea, making it the thinnest area of the retina and affording its tightly packed cone photoreceptors (147,000/ mm2 ) optimal exposure to incident light. The photoreceptors are the sensory receptors of the retina, the bipolar cells, situated in the inner retina, are the first order neurons and the retinal ganglion cells (RGC), situated in the innermost layer, are the second order neurons. The RGC axons traverse the surface of the retina in the nerve fibre layer on the surface of the retina and then travel within the optic nerve to synapse
593 CHAPTER THIRTY stimulated by vascular endothelial growth factor (VEGF-A) and insulin-like growth factor (IGF-1), which work synergistically. VEGF production is induced by physiological fetal retinal hypoxia, whilst IGF-1 is oxygen independent, with rising levels stimulating retinal angiogenesis during the second and third trimesters. Retinopathy of prematurity (ROP) is a neovascular disorder affecting infants born at less than 32 weeks’ gestational age. Extremely low birth weight (<1000 g) and early supplemental oxygen requirement and acidosis are additional important risk factors. About 50% of premature babies born <1000 g birth weight will develop ROP and 15% will reach the threshold for treatment. In the UK, guidelines specify that all babies under 32 completed weeks’ gestation and less than 1500 g should be screened by an ophthalmologist. ROP develops in two distinct phases: • The hyperoxic phase: premature delivery into a high oxygen environment causes down-regulation of VEGF, halting the normal progression of vascular tissue into the developing anterior retina • The hypoxic phase: the unvascularized anterior retina becomes increasingly ischaemic as it matures, VEGF is up-regulated and leads to neovascularization from the ridge of mesenchymal spindle cells at the anterior border of the vascularized retina. Untreated, the abnormal new vascular network creates a tractional retinal detachment and blindness. The international classification of ROP includes stages of ROP development and zones of location in the retina (Fig. 30.4). Zone 1 and posterior zone 2 ROP is the most aggressive. The threshold for treatment is based on the zone of the disease, its stage, and the presence of retina vascular dilatation and tortuosity – ‘plus’ disease. Timely treatment can prevent progression to retinal detachment and blindness. Recently, a correlation between a drop-off in postnatal weight gain (which mirrors a fall in IGF-1 levels) and the subsequent development of ROP has been identified. A computer-based algorithm based on postnatal weight gain (WINROP) is being developed, which may help future identification of those babies most at risk. Currently, laser ablation of the avascular, ischaemic anterior retina is the preferred treatment for severe ROP. A promising new treatment is the intra-vitreal injection of an anti-VEGF agent (bevacizumab or ranibizumab). Although this treatment is easier and quicker to perform than laser, systemic absorption depresses serum VEGF levels for several weeks, which may have systemic consequences. The resultant prolonged absence of VEGF within the eye also delays the in the lateral geniculate body. For optimal light transference to the underlying photoreceptors, the RGC axons are only myelinated distal to the optic disc, so that they remain transparent. Sometimes the myelination process occurs anterior to the optic disc, giving a white appearance to the nerve fibre layer; although striking in appearance, myelinated nerve fibres rarely cause visual problems unless they involve the macula. Methods of visualizing the fundus • Direct ophthalmoscope • Indirect ophthalmoscope • Retcam imaging • Ocular coherence tomography • Standard retinal photography • Fluorescein angiography Although portable and cheap, the direct ophthalmoscope is the most difficult method of visualizing the fundus in children: it gives a real, magnified image but small field of view with no depth, making fundoscopy difficult in young children. In this situation, the head-mounted indirect ophthalmoscope is the instrument of choice, giving a stereoscopic, less magnified image with a much wider field of view. The virtual nature of the image, inverted both vertically and horizontally, can be confusing for the novice and the technique can take years to master. The Retcam is a wide-angle camera, which can usefully document the fundus appearance and is particularly useful for retinopathy of prematurity and retinal haemorrhages secondary to inflicted head injury. Its drawback is that the camera lens makes contact with the cornea, making it poorly tolerated in alert babies and toddlers. Most children over 5 years of age are able to sit still for standard retinal photography. Ocular coherence tomography has been a great advance in retinal imaging, enabling a detailed crosssectional image of the retina and optic disc to be constructed. This can be particularly helpful when macular pathology is suspected or to document changes over time, for instance, serial nerve fibre layer thickness analysis in papilloedema. Intravenous fluorescein angiography is useful for demonstrating the vascular network of the retina, particularly areas of ischaemia or vascular leakage. Once visualized by fluorescein angiography, the areas of retinal ischaemia can be lasered to prevent secondary neovascularization. Prematurity and the eye Retinopathy of prematurity Vascularization of the retina begins at about 14 weeks’ gestation and is not complete until term. It is
30 594Ophthalmology Fig. 30.4 Stages and zones in retinopathy of prematurity. A. This Retcam image shows stage 3 ROP with a neovascular ridge in the temporal retina of a left eye; the avascular, ischaemic retina lies anteriorly. B. This Retcam image shows aggressive posterior ROP (APROP) in zone 1 of a left eye. The neovascular tissue in APROP lies flat on the retina rather than forming a ridge, which can make identification difficult. Note the vascular tortuosity and dilatation signalling ‘plus’ disease. Stages of retinopathy of prematurity (ROP) Zones of ROP (left eye) Stage 1: Demarcation line at anterior edge of vascularized retina Stage 2: The line becomes a thickened ridge Stage 3: The ridge develops neovascularization Stage 4: Localized tractional retinal detachment Stage 5: Funnel retinal detachment Aggressive posterior ROP (APROP): Zone 1 disease, neovascularization is not localized to a ridge Plus disease: Dilatation and tortuosity of the retinal vessels Zone 1 Zone 2 Zone 3 Disc Fovea Vascular tortuousity in APROP Stage 3 ridge, posterior zone 2 Avascular retina A B Question 30.1 Ocular structures The following (A–J) are ocular structures: A. Aqueous B. Ciliary body C. Cornea D. Lens E. Optic nerve head F. Retina G. Retinal pigment epithelium H. Trabecular meshwork I. Uveal tract J. Vitreous gel Which tissue is the primary site of pathology in the following conditions? Select ONE answer for each. Each answer may be used once, more than once or not at all. 1. Toxoplasma choroiditis 2. Infantile glaucoma 3. Accommodative insufficiency Answer 30.1 1. I. Uveal tract. The choroid is part of the uveal tract and is the site of ocular toxoplasma infection. 2. H. Trabecular meshwork. The primary cause of infantile glaucoma is a congenital anomaly of the trabecular meshwork; eventually breaks in Descemet’s membrane of the cornea and optic nerve damage in addition to globe enlargement occur. 3. B. Ciliary body. Accommodation is centrally mediated and stimulated by vision de-focus. Insufficient contraction of the ciliary body prevents the lens from becoming more globular and powerful. In adults, accommodative insufficiency occurs beyond the age of 45 years due to the aging lens losing its malleability, but this is not the case in children.
595 CHAPTER THIRTY Management of childhood cataract Visually significant congenital cataracts require early surgery within the first two months of life to achieve good visual function. Less dense cataracts may be managed conservatively with close observation and refractive correction. If the cataracts are unilateral or asymmetrical, occlusion therapy (patching) of the better-seeing eye may be prescribed. Infants and children develop especially severe ocular inflammation and fibrotic changes following intra-ocular procedures. To prevent re-opacification of the visual axis with scar tissue, the posterior capsule and anterior vitreous are removed during the lensectomy procedure and an intensive topical steroid regimen is prescribed postoperatively. Some paediatric ophthalmologists elect to implant the eye with an acrylic intra-ocular lens (IOL) at the time of lensectomy if the globe is otherwise normal; others leave the eye aphakic (without a lens) and replace the refracting power of the lens with a contact lens until the child is older. Since they are not exchangeable, an IOL refractive power is selected to leave the eye hypermetropic, to allow for the physiological myopic shift which occurs during ocular growth. This residual hypermetropia is usually corrected with an extended wear contact lens for the first year and glasses thereafter. Childhood glaucoma Childhood glaucoma is a rare, potentially blinding condition characterized by raised intra-ocular pressure and optic disc cupping. In the normal optic nerve head, the retinal ganglion cell (RGC) axons are concentrated around the circumference of the optic disc, leaving a pale central area relatively devoid of axons, called the optic cup. The raised intra-ocular pressure of glaucoma causes RGC death and, as the number of axons passing through the optic nerve head opening dwindles, the relative size of the optic cup (the cup:disc ratio) gradually enlarges. Uncontrolled glaucoma will result in peripheral visual field loss, which is difficult to detect in children. The RGCs serving the macula are the last to be damaged; this is why the optic neuropathy associated with glaucoma is not characterized by the early loss of visual acuity or colour vision that is seen with optic neuritis or optic atrophy. The normal intra-ocular pressure in children is usually between 6 and 18 mmHg and can usually be measured in the eye clinic. Raised intra-ocular pressure is the result of impaired aqueous outflow through the trabecular meshwork rather than overproduction of aqueous by the ciliary body. Children under 3 years of age have low scleral rigidity, and raised intra-ocular pressure will result in globe expansion (buphthalmos); the increase in axial length causes a shift towards normal vascularization of the anterior retina, leaving it non-perfused and ischaemic for months beyond term. In the UK, anti-VEGF treatment is currently reserved for the most severe cases in which laser treatment is not possible or sufficiently effective. Randomized, controlled trials are planned to determine the safety of this new treatment. Congenital and developmental eye conditions Childhood cataract Cataracts may be present at birth or develop and become visually significant with time. The lens grows in size throughout life as layer upon layer of lens fibres are laid down, encircling the fetal and embryonic nucleus like layers of an onion. The lens has the highest protein content of any tissue in the body and is transparent because of the accurate organization of the proteins (called crystallins) in fibres within it; disorganized protein fibre structure or the accumulation of abnormal metabolic products within the lens causes opacification. Congenital cataract Cataracts occur in 2/10,000 live births and are usually identified at screening. Although the majority are idiopathic, 20% of children with isolated bilateral congenital cataracts will have a family history or parental consanguinity; the cataracts are often secondary to point mutations (in genes such as MAF, CRYA1). Cataracts are common features of many different syndromes, particularly Down’s syndrome (1.5% prevalence); they may also complicate other ocular malformations, such as aniridia. Babies with sporadic bilateral congenital cataracts should have a TORCH and galactosaemia screen and a referral for genetic evaluation. Males should additionally have a urinary amino acid assessment to exclude Lowe syndrome. Unilateral congenital cataracts most commonly result from abnormal regression of the embryological hyaloid vascular system, which supplies the posterior lens during development (persistent fetal vasculature). Unilateral cataracts are usually associated with mild microphthalmia and are not generally investigated. Cataracts developing after the critical period of neuroplasticity (see Chapter 4, Normal child development) are usually associated with a better visual prognosis. These may be genetic in aetiology but may also be secondary to uveitis, steroid therapy and radiation.
30 596Ophthalmology Retinal pathology due to nonaccidental head injury The tangential acceleration/de-acceleration injury to which an infant may be subjected in non-accidental injury can result in vascular shearing – in the brain, this results in subdural haemorrhage; in the retina it causes multiple, multi-layer haemorrhages and retinoschisis (splitting of the layers of the retina). Multiple retinal haemorrhages, especially when associated with subdural haemorrhage, are characteristic of (but not specific to) non-accidental head injury. Clotting and metabolic conditions, such as glutaric aciduria, should be excluded. The presence of retinoschisis and perimacular folds indicate significant vitreous traction, which may be the result of severe accidental or non-accidental head injury. Patterns of retinal injury (Fig. 30.5) are: • Dark, round sub-retinal haemorrhages, often with a white centre, occur in the potential space between the retina and RPE (resolve within months) • Dot- and blot-shaped intra-retinal haemorrhages (resolve within weeks) • Flame-shaped nerve fibre layer haemorrhages (resolve within days) • Pre-retinal (sub-hyaloid) haemorrhages lie in the potential space between the posterior hyaloid (vitreous) surface and the retina. The retina beneath is obscured by the haemorrhage and there is often a blood fluid level. myopia (or loss of hypermetropia) and an increasing corneal diameter (normal corneal diameter is 11 mm). Primary congenital glaucoma Presenting within the first year of life, this is usually bilateral, and results from abnormal development of the drainage angle. Incidence is 1/10,000 live births and the majority are due to a gene mutation (in the CYP1B1 gene). The globe enlarges due to the raised pressure and splits occur in the deeper layers of the cornea (Haab’s striae) leading to photophobia and corneal opacification. Treatment is by the early surgical division of the abnormal ‘Barkan membrane’ which obstructs fluid flow to the drainage angle. Secondary glaucoma Causes of secondary glaucoma are: • Anomalies of the anterior segment, e.g. aniridia • Sturge–Weber syndrome: if the capillary malformation involves the eyelids, the episcleral venous pressure may be raised, reducing aqueous outflow and causing glaucoma in 50% • Following congenital cataract surgery (30% lifetime risk), possibly due to the release of vitreous derived factors or inflammatory cells into the drainage angle in infancy • Topical, inhaled or oral steroid therapy: due to the increased accumulation of glycosaminoglycans or trabecular meshwork-inducible glucocorticoid response protein (TIGR) in the trabecular meshwork. Fig. 30.5 Retinal findings in severe non-accidental head injury. This Retcam photo of the right eye shows severe multilayer retinal haemorrhages and a marked perimacular fold with retinoschisis (retinal splitting) at the macula. Sub-retinal haemorrhages Deep retinal haemorrhages Perimacular folds Nerve fibre layer haemorrhages
597 CHAPTER THIRTY mutations have been implicated in the development of retinal and macular dystrophy, which are currently untreatable and responsible for a quarter of all childhood blindness in the UK. Retinal dystrophies can develop at any stage in childhood. In general terms, they can be non-progressive, for instance due to a channelopathy, or progressive, for instance due to ongoing cell death from the accumulated toxic metabolic products, e.g. RDS gene mutation in autosomal dominant retinal dystrophy. Rod dystrophies cause poor peripheral and night vision (nyctalopia), cone dystrophies cause poor colour vision and visual acuity, often with photophobia (due to defective light adaptation). Macular dystrophies affect the macula only, causing poor central and colour vision but sparing the peripheral visual field. The visual pathway The anterior visual pathway Isolated damage to the optic nerves, optic chiasm and optic tract produce characteristic visual field defects (Fig. 30.6): bitemporal hemianopia caused by chiasmal lesions, homonymous hemianopia caused by lesions of the optic tract, optic radiation and occipital cortex. In practice, however, the visual field deficit is • Vitreous haemorrhage, caused by the rupture of a pre-retinal haemorrhage into the vitreous • Retinoschisis and perimacular folds: infant vitreous is viscous and strongly adherent to the retina; severe vitreous traction causes a splitting of the inner retinal layers, elevating the retina into folds encircling the macula. Retinal dystrophies The phototransduction cascade Phototransduction is the process by which light is converted into electrical signals. The electrical transmission of the light response can be assessed using an electrodiagnostic test called an electroretinogram. This investigation first tests the rod pathway after dark adaptation using a dim light to which cones are insensitive, then the cone pathway after light adaptation to a bright flash and flicker light stimulus (to which rods are unable to respond). The phototransduction pathway relies on many proteins, and therefore retinal dysfunction due to mutation or deletion of genes encoding these proteins is common. Eight per cent of males are affected by mutations of the cone pigments, which alter their spectral sensitivity (congenital colour blindness). More significantly, hundreds of different gene Fig. 30.6 The visual pathway. The temporal retina of the right eye and nasal retina of the left eye serve the left visual field. Axons from the nasal retina decussate at the optic chiasm and thereafter axons serving the left visual field travel together in the optic tract and radiation. Visual field deficit resulting from pathology at each point in the pathway is shown on the right. Posterior lesions produce more congruous (similar) homonymous field deficit than anterior lesions. The anatomy of the pupillary light reflex is illustrated on the left. Pupillary fibres leave the optic tract and synapse in the pretectal nuclei of the midbrain. The parasympathetic nucleus of the IIIrd nerve receives bilateral innervation and its fibres supply the pupil sphincter after synapsing in the ciliary ganglion. Lesions of the visual pathway and expected visual field deficit Light reflex pathway Lesion 1: Right optic nerve lesion Poor vision right eye, central scotoma Lesion 2: Chiasmal lesion Bitemporal hemianopia Lesion 3: Right optic tract lesion Incongruous left homonymous hemianopia Lesion 4: Right optic radiation lesion Congruous left homonymous hemianopia Light reflex Ciliary ganglion Midbrain EdingerWestphal nucleus Pretectal nucleus Visual cortex Lateral geniculate body 2 1 3 4
30 598Ophthalmology Parietal lesions cause inaccuracy of voluntary saccadic and pursuit eye movements (visual ataxia). Functions of the ventral stream are: • Route finding • Word/letter face recognition • Recognizing expression Right temporal lobe injury causes poor recognition of people (prosopagnosia). Left temporal lobe injury causes impaired shape recognition (dyslexia). Cerebral visual impairment Cerebral visual impairment (CVI) accounts for 30% of SVI registrations in the UK and is usually associated with other developmental and motor deficits. The term encompasses impaired visual acuity, visual field deficit and abnormalities of perceptual and cognitive visual function secondary to brain pathology. CVI can result from: • CNS developmental defects such as holoprosencephaly (failed or incomplete separation of the forebrain) • Perinatal insults – Prematurity, e.g. periventricular leukomalacia (PVL), intraventricular haemorrhage – Term infants: hypoxic–ischaemic encephalopathy • Older children: hypoxia, trauma, visual pathway tumours, metabolic encephalopathy Ex-premature babies with PVL have visual ataxia and poor processing of complex visual environments (damage to the dorsal stream) and also bilateral inferior homonymous hemianopia (damage to the superior fibres of the optic radiation). These children often have bilaterally pale, cupped but normal sized optic nerve heads due to trans-synaptic, retrograde degeneration of the RGCs secondary to axon injury within the optic radiation. rarely so clear cut. For instance, a child with an optic chiasmal glioma may have a bitemporal hemianopia due to chiasmal involvement, but anterior extension into the optic nerve may leave the child with functional vision in the contralateral nasal hemifield only. The posterior visual pathway The optic radiations originate in the neurons of the lateral geniculate nucleus (LGN); neurons from the lateral portion of the LGN, conveying the homonymous superior visual field, fan out laterally and inferiorly around the tip of the inferior horn of the lateral ventricle and swing posteriorly, terminating in the inferior lip of the calcarine fissure of the occipital cortex. Neurons from the medial portion of the LGN, conveying the homonymous inferior visual field, pass almost directly posteriorly, in the retrolentiform part of the internal capsule before terminating in the superior lip of the calcarine fissure of the occipital cortex. The visual cortex consists of the primary and secondary visual area situated, for the most part, on the deep calcarine sulcus on the posteromedial surface of the hemisphere. The macular area is represented in the most posterior third of the visual cortex. Dorsal and ventral streams of visual processing Visual processing and cognitive visual function occur via white matter connections linking visual cortex with the posterior parietal cortex (the dorsal stream) and the inferotemporal cortex (the ventral stream). Functions of the dorsal stream are: • Visual searching • Attention to detail in a complex visual environment • Visual guidance of actions Fig. 30.7 The optics of the eye with refractive error. A. Myopia: image focused anterior to the retina, corrected with concave (minus) lens. B. Hypermetropia: image focused posterior to the retina, corrected with convex (plus) lens. A B
599 CHAPTER THIRTY Question 30.2 Diplopia and headaches after reading A 7-year-old systemically well child with good visual acuity and no refractive error has developed intermittent horizontal diplopia associated with headaches after reading over the last few months. Eye movement testing shows a full range of eye movements, with no movement on cover testing for distant targets but an exotropia (divergent squint) for near targets. Which diagnosis is the more likely? Select ONE answer only. A. Bilateral sixth nerve palsy B. Convergence insufficiency C. Dyslexia D. Myasthenia gravis E. Uncorrected hypermetropia (long sight) period of visual neuroplasticity (see Chapter 4, Normal child development). Refractive error Myopia (short-sightedness) occurs when either the refracting power of the lens is too strong or, more commonly, when the eye is long in proportion to the refracting power of the lens (Fig. 30.7). A concave lens is required to achieve a focused image on the retina. Hypermetropia (long-sightedness) occurs when either the power of the lens is too weak (or absent – aphakia) or the eye is short in proportion to the refractive power of the eye (see Fig. 30.7). Astigmatism occurs usually because the cornea has a steeper curvature and refractive power in one meridian, which leads to a blurred focal point. Anisometropia refers to presence of unequal refractive states in each eye. Accommodation The triad of the near reflex includes accommodation, miosis (pupil constriction) and convergence. Near image de-focus causes parasympathetic stimulation of the ciliary muscle and the sphincter pupillae, releasing zonular tension on the lens and allowing it to become more globular and powerful. Accommodation is temporarily paralysed using topical antimuscarinic agents Question 30.3 Abnormal ocular findings The following (A–J) is a list of ocular findings: A. Anisocoria B. Buphthalmos C. Enophthalmos D. Incomitant strabismus E. Keratitis F. Lagophthalmos (poor or incomplete lid closure) G. Microphthalmia H. Proptosis I. Ptosis J. White blood cells in the anterior chamber Choose the most likely ocular finding which accompanies the following pathologies. Select ONE answer for each. Each answer may be used once, more than once or not at all. 1. Bilateral sixth nerve palsy 2. Unilateral seventh nerve palsy 3. Positive anti-nuclear antibody Answer 30.2 B. Convergence insufficiency. Convergence insufficiency is a relatively common problem in school-aged children and refers to a reduced ability to converge the eyes on near targets. This causes symptoms of eye strain and diplopia when reading. Bilateral sixth nerve palsy would cause an esotropia (eye turns inwards) for distance targets. Uncorrected hypermetropia is excluded by the normal refraction. Myasthenia gravis causes variable ptosis and diplopia with fatiguability; the absence of ptosis in this case makes this diagnosis unlikely. Dyslexia does not cause squint. Optics The normal refractive state of the eye Focusing a distant image in an optical system of 22 mm requires 50 dioptres (D) of refractive power. In the human eye, about 44D is provided by the cornea and the rest is provided by the lens. The lens is malleable and becomes more globular with accommodation, thereby increasing its power and allowing near objects to be focused on the retina. Most infants are hypermetropic, a gradual process of emmetropization occurring in the first 5 years. Amblyopia is poor vision in one or either eye which persists once any existing ocular or refractive anomaly is corrected. It is usually unilateral and results from visual deprivation (e.g. congenital cataract), strabismus or refractive error. Amblyopia may occur and be treated within the
30 600Ophthalmology Table 30.1 The cranial nerves supplying the orbit Cranial nerve Structure innervated Main action on the eye Result of dysfunction III Oculomotor ‘Down and out’ eye with ptosis Superior division Levator palpebrae superioris Superior rectus (SR) Upper lid elevation Elevation Ptosis Poor elevation Inferior division Medial rectus (MR) Inferior rectus (IR) Inferior oblique (IO) Adduction Depression Elevates the adducted eye, outward rotation Poor adduction Poor depression IV Trochlear Superior oblique (SO) Depresses the adducted eye, inward rotation Problems reading/going downstairs Reduced depression in the adducted eye, head tilt V Trigeminal sensory Conjunctival, cornea, iris and uveal tissue, facial skin Provides sensation Corneal anaesthesia, facial numbness VI Abducens Lateral rectus Abduction Poor abduction, convergent squint VII Facial Orbicularis oculi Lid closure Poor lid closure, paralytic ectropion Parasympathetic (via III) Pupillary sphincter Ciliary muscle Miosis (small pupil) Accommodation Adie pupil: Poorly reacting large pupil, poor near vision Sympathetic (via VII) Pupil dilators, iris melanosomes Mydriasis (large pupil), iris pigmentation Horner syndrome: Small pupil which dilates poorly in dark Lighter iris (heterochromia) if congenital Müller muscle of lids Mild upper and lower lid retraction Mild upper and lower lid ptosis, pseudo-enophthalmos in order to objectively measure refractive error. The ability to accommodate decreases exponentially with age and requires virtually no effort in infancy whilst being irretrievably lost at the age of about 45 due to increasing lenticular rigidity. Innervation of the eye and ocular motility Six extra-ocular muscles control eye movement and these are supplied by cranial nerves III–VI. An aide Answer 30.3 1. D. Incomitant strabismus. Bilateral sixth nerve palsies cause an esotropia (one or both eyes turn inward) in primary position and poor abduction of each eye. This is a common false localizing sign of raised intracranial pressure in children. 2. F. Lagophthalmos (poor or incomplete lid closure). The VIIth nerve innervates orbicularis oculi – this causes incomplete lid closure and corneal exposure. 3. J. White blood cells in the anterior chamber. Juvenile idiopathic arthritis with positive antinuclear antibody may cause a painless chronic anterior uveitis, which allows white cells to leak into the aqueous humour. memoir is LR6(SO4) (Table 30.1). Conjugate movement of each eye is necessary so that the image falls on identically corresponding positions on each retina. This necessitates fine coordination of all 12 muscles within the CNS. Visual feedback of de-focus and transient diplopia permits fine adjustments to be made, a cerebral process called fusion. Laws of innervation Hering’s law During purposeful eye movement, equal and simultaneous stimulation of the yoke muscles is required. There are six sets of yoke muscles, as shown in Figure 30.8. For instance, a boy with a right sixth nerve palsy will tend to use the left eye to fixate the examiner and the right eye will have a convergent squint. If asked to fixate with the paretic right eye, additional stimulation will flow to the right lateral rectus to try to keep the eye straight. The yoke muscle, the left medial rectus, will similarly receive additional stimulation causing additional overaction and a larger squint angle. Sherrington’s law of reciprocal innervation In the eye, stimulation of the agonist muscle must be accompanied by inhibition of its antagonist to allow movement.
601 CHAPTER THIRTY Fig. 30.8 The nine positions of gaze and six pairs of yoke muscles. SR: Superior Rectus; IO: Inferior oblique; LR: Lateral Rectus; MR: Medial Rectus; IR: Inferior Rectus; SO: Superior obleque. Right gaze Dextro-elevation: Right SR, Left IO Elevation Laevo-elevation: Left SR, Right IO Dextro-version: Right LR, Left MR Primary position Laevo-version: Left LR, Right MR Dextro-depression: Right IR, Left SO Depression Laevo-depression: Left IR, Right SO Left gaze Concomitant squints Most childhood ocular misalignment is concomitant, i.e. the squint angle is the same in all positions of gaze and is due to refractive error, accommodation issues or poor cortical fusional mechanisms. Hypermetropic children accommodate when not wearing glasses in order to keep targets focused. The power of accommodation declines exponentially from birth and, at the age of 2–3 years, when the child is doing more detailed close viewing, the resultant accommodative strain stimulates over-convergence and a convergent squint (esotropia). In order to prevent diplopia, the child sacrifices binocularity for clarity and a process of cerebral visual suppression in one eye occurs, subsequently leading to amblyopia. Early correction with glasses can restore binocularity and prevent amblyopia. Myopic children tend to have weaker accommodation; their problem is too much refracting power in their eyes. This weakened accommodation can lead to poor accommodative convergence and they have a tendency to develop a divergent squint (exotropia). Children with poor vision in one eye, for instance due to retinoblastoma or cataract, will tend to develop an early squint. For this reason, fundoscopy should be attempted in all children who present with a squint. Children with developmental delay and cerebral palsy have poor cortical fusion mechanisms and are at high risk of developing a squint and amblyopia. Incomitant squints Cranial nerve palsy will cause an incomitant squint, i.e. the squint angle changes depending on the position of gaze. This may occur due to a congenital dysinnervation syndrome (e.g. Duane syndrome), or may be acquired though trauma or tumour. Raised intracranial pressure commonly causes VIth nerve paresis in children; a recent onset squint and diplopia in a child merits fundoscopy. Children with cranial nerve palsies are at risk of developing strabismic amblyopia and those young enough to be in their neuroplastic period need referral to an ophthalmologist for amblyopia management. Clinical investigation of squint Ocular misalignment can be detected using the cover test. Manifest deviations can be identified by studying the corneal light reflections, which will appear displaced to the nasal side of the pupil in an exotropic eye and towards the lateral side of the pupil in an esotropic eye. Covering the fixating eye (cover test) will cause a corrective movement in the squinting eye (inwards in exotropia and outwards in esotropia) to enable it to take up fixation. Latent squints are more difficult to identify and require interruption of binocular fusion by the uncover and alternating cover test. When either eye is covered, the covered eye will drift into misalignment and the recovery motion will be seen when the cover is removed. Management of squint Optical correction of refractive error and amblyopia therapy are central to squint management in children. Once amblyopia is treated, surgical management of the squint can proceed. The main techniques involve weakening muscles by moving the insertion of the muscle posteriorly (recession) or tightening muscles by making them shorter (resection). The majority of squint operations are cosmetic; about 20% are functional, aimed at restoring a child’s binocularity. Sometimes, particularly in the complex incomitant squints seen with CNS tumours, surgery is not helpful and prismatic glasses or the occlusion of one eye may be the only solution to intractable diplopia.
30 602Ophthalmology causing slow conjugate eye movement to the right. • Rotational testing: hold the baby at arm’s length with his/her head tipped forward slightly, if possible. As the infant is slowly rotated, the eyes will deviate towards the direction of the spin, with a re-fixational jerk nystagmus to the opposite side. Vertical gaze Projections from the frontal eye fields, vestibular apparatus and PPRP innervate the rostral interstitial nucleus of the MLF, which lies dorsomedial to the red nucleus in the midbrain. From here, control of upward saccades passes dorsally through the posterior commissure to the IIIrd nerve nuclei. Control of downwards saccades passes dorsally and caudally to the IIIrd and IVth nerve nuclei. Transient benign tonic downgaze deviation of both eyes (with normal upward movements on doll’s head testing) can be seen in normal neonates and resolves within months. The ‘sun-setting’ sign is a tonic downward deviation of the eyes secondary to aqueductal distention from hydrocephalus; upward saccades cannot be generated by doll’s head movement. Dorsal midbrain (Parinaud’s) syndrome causes a supra-nuclear paresis of vertical gaze, often with light–near dissociation and convergence–retraction nystagmus. Inter-nuclear control of conjugate horizontal eye movement The horizontal gaze centre – the paramedian pontine reticular formation (PPRF) – receives supra-nuclear stimulation from the eye movement centres and coordinates the innervation between the ipsilateral VIth nerve nucleus and the contralateral medial rectus subnucleus of the IIIrd nerve. The inter-nuclear fibres travel within the medial longitudinal fasciculus (MLF) and may be damaged by Arnold–Chiari malformaltion (downward displacement of the cerebellar tonsils), hydrocephalus, fourth ventricle and brainstem tumours and trauma. • PPRF lesions cause a palsy of conjugate horizontal gaze towards the side of the lesion. • MLF lesions cause ipsilateral absence of adduction and nystagmus in the abducted contralateral eye (aide memoir: iPAD – ipsilateral poor adduction). • PPRF and ipsilateral MLF lesions cause one-and-ahalf syndrome, an ipsilateral absence of adduction and an ipsilateral horizontal gaze palsy (the only horizontal movement is abduction with nystagmus of the contralateral eye). Supra-nuclear control of eye movements Horizontal gaze Voluntary saccadic eye movements Conjugate saccades towards one side are mediated by the contralateral fronto-mesencephalic pathway (from the frontal eye field via the superior colliculus to the PPRF). Frontal lesions cause tonic deviation of the eyes towards the side of the lesion due to the unbalanced input from the other hemisphere. Voluntary pursuit eye movements Conjugate pursuit movements towards one side are mediated by the ipsilateral parieto-occipital mesencephalic pathway via the PPRF. Deep parietal lesions cause disrupted pursuit towards the side of the lesion. Vestibular eye movements These are mediated by the contralateral labyrinthine– pontine pathway and can be useful for assessing brainstem and VIth nerve function: • Doll’s head manoeuvre: sudden rotation to the left stimulates the left horizontal semicircular canal Question 30.4 Lack of eye contact at 9 weeks An infant is seen at the 9-week baby check and her mother is concerned that her baby is not maintaining eye contact with her. There is no family history of eye problems and, in other respects, the infant is developing normally. During your examination, the baby stares at light but does not follow a large target well; horizontal nystagmus is present but the red reflex is normal. What is the most appropriate management plan? Select ONE answer only. A. Advise the mother that you will organize an optometric assessment B. Arrange a routine orthoptic assessment C. Arrange for the child to attend the emergency eye clinic D. Reassure the mother and arrange a review in a month to reassess the visual development E. Refer the baby for an urgent appointment for paediatric ophthalmic assessment
603 CHAPTER THIRTY Infantile nystagmus Infantile nystagmus is often noticed by the parents in the first few months of life. It has several characteristic features: • Usually horizontal (but can be vertical or rotatory), uniplanar, i.e. does not change plane in different positions of gaze • Usually jerk but may be pendular • Conjugate and similar in amplitude in both eyes • May have associated head oscillation • Null point of gaze where the nystagmus is less marked. The child will often adopt a head posture to put his/her eyes in that position of gaze • Nystagmus is usually dampened by convergence, so near vision is better than distance vision • Nystagmus worsens when one eye is covered Infants with nystagmus should be seen by an ophthalmologist to exclude a causative ocular abnormality. If the child’s visual development, eye examination, visual electrodiagnostics and general development are normal, idiopathic motor nystagmus (IMN) is diagnosed. X-linked IMN may result from gene mutations in FRMD7. Acquired nystagmus due to neurological disease Disconjugate nystagmus should trigger concern about potential neurological disease. The pattern of nystagmus can help to localize the pathology. • See-saw nystagmus: pendular, one eye elevates and rotates inwards while the other eye depresses and rotates outwards. Causes: supra-sellar and rostral midbrain lesions. • Upbeat nystagmus: jerk, vertical with fast phase upwards. Causes: lesions of the cerebellar vermis and brainstem • Downbeat nystagmus: jerk, vertical with fast phase downwards. Causes: lesions of the cervico-medullary junction at the level of the foramen magnum, e.g. Arnold–Chiari malformation. • Periodic alternating nystagmus: jerk, horizontal with fast phase alternating from one side to the other after a short rest period. Causes: Arnold–Chiari malformation, spinocerebellar degeneration, trauma, posterior fossa tumours. • Spasmus nutans: triad of head turn, head nodding and nystagmus. Benign form occurring within first 18 months and resolves by 3 years. Nystagmus can be horizontal, vertical, pendular and dysconjugate. Nystagmus Descriptive terms used in documenting nystagmus Nystagmus is a rhythmic oscillation of the eyes and may be described using the following terms: • Type: – Pendular: phases of equal velocity – Jerk: phases of unequal velocity • Direction: the direction of the fast component • Plane: horizontal, vertical, rotatory • Amplitude: coarse, medium, fine • Rate: slow, fast • Conjugacy: both eyes demonstrate the same movement • Null zone: a point of gaze in which the nystagmus intensity is minimal Physiological nystagmus Nystagmus can be physiological; types include optokinetic nystagmus, rotational nystagmus, caloric nystagmus or end-point nystagmus (seen at extremes of gaze or after sustained deviation of the eyes). Gazeevoked nystagmus can often be seen as a consequence of therapeutic doses of anti-convulsants. Pathological nystagmus Causes of nystagmus fall into three major categories: • Infantile sensory nystagmus (due to poor vision/afferent system problems, e.g. aniridia, albinism) • Infantile idiopathic motor nystagmus (the most common form with otherwise normal ocular and neurological function) • Acquired nystagmus secondary to neurological disease • Acquired vestibular nystagmus Answer 30.4 E. Refer the baby for an urgent appointment for paediatric ophthalmic assessment. Parents’ concerns regarding visual development should always be taken seriously and the nystagmus in this case is a worrying feature warranting early referral rather than routine review. It is inappropriate for this baby to be seen by an orthoptist, optometrist or in the emergency eye clinic – an urgent consultation with a paediatric ophthalmologist is required.
30 604Ophthalmology present in one eye, both pupils will constrict equally when light is directed towards the normal eye but neither pupil will constrict when light is shone in the eye with no perception of light (this situation is rare in practice). If there is a relative afferent pupillary defect (RAPD), both pupils will still constrict consensually, but this constriction will be less marked when the light is directed towards the eye with afferent pathway pathology compared to the normal eye. As the light is swung from normal eye to the eye with afferent pathology, a relative dilatation of both pupils will be seen. Efferent pathway Parasympathetic innervation of the pupil The parasympathetic autonomic system is the efferent pathway of the light and near response. A unilateral defect in the parasympathetic innervation of the pupil will lead to anisocoria (unequal pupils). The affected pupil is larger than its partner and unresponsive to light and accommodation, e.g. Adie pupil, complete third nerve palsy. The efferent outflow from the Edinger–Westphal nucleus is under cortical inhibition; pupils are relatively miosed during sleep and sedation but arousal and seizure activity increase the inhibitory tone, resulting in larger pupils. Sympathetic innervation of the pupil The sympathetic autonomic system innervates the dilating muscle of the pupil. Horner syndrome results from ipsilateral injury to the sympathetic chain. The unbalanced action of the pupil sphincter results in a small pupil and a mild upper and lower lid ptosis. If the injury occurs in the perinatal period, e.g. due to forceps injury to the neck, the affected eye will be lighter in colour than its partner (heterochromia). If the lesion is pre-ganglionic, there will be accompanying anhydrosis. Sympathetic innervation occurs via a three neuron chain: • First order neuron: from hypothalamus to ciliospinal centre of Budge (syringomyelia, cerebrovascular accident) • Second order neuron: from cilio-spinal centre of Budge to superior cervical ganglion (chest and neck lesions including neuroblastoma) • Third order neuron: from superior cervical ganglion via the ophthalmic division of the trigeminal nerve to the pupil dilator muscle and Müller muscle of the eyelids (cavernous sinus lesion, migraine variants) These features can be mimicked by chiasmal, suprachiasmal or third ventricle tumours. • Convergence–retraction nystagmus: jerk convergence–eye retraction movements on attempts of upgaze. Usually associated with defective upgaze and light–near dissociation as part of dorsal midbrain syndrome. • Opsoclonus: bursts of rapid, multivectorial, chaotic and conjugate eye movement abnormality. May be associated with myoclonus: ‘dancing eyes and dancing feet’. May occur after infectious encephalopathy but can be a presenting nonmetastatic feature of occult neural crest tumours, e.g. neuroblastoma. • Ocular bobbing: fast conjugate vertical movements with fast phase downwards. May be seen in metabolic encephalopathy or obstructive hydrocephalus. • Cerebellar system disease: gaze-evoked nystagmus, ocular dysmetria and visual fixation instability. Acquired vestibular nystagmus This is usually associated with other symptoms such as deafness, tinnitus and vertigo. Vestibular disease causes a horizontal-rotatory primary position unidirectional jerk nystagmus. The fast phase beats away from the diseased vestibular system. Pupil light responses Pupil size is dependent on an afferent stimulus (light and/or accommodative convergence) and on the efferent sympathetic and parasympathetic innervation pathways. Afferent pathway Approximately 10% of the axons in the optic tract synapse in the midbrain. There, they innervate both the ipsilateral and contralateral Edinger–Westphal nucleus. This arrangement leads to consensual pupil reactions to light, i.e. anisocoria (unequal pupils) cannot result from a defect in the afferent pathways (see Fig. 30.6). A defect in the afferent pathway can be the result of retinal disease or pathology affecting the optic nerve and/or anterior optic tract. A very useful test in clinical practice is the Marcus Gunn (or swinging torch) test, which compares the afferent pathway of each eye. For this test, the child should be looking at a distant target (to prevent miosis due to the near reflex). Both pupils will be the same size due to the consensual light response. If a complete afferent pupillary defect is
605 CHAPTER THIRTY When a drop is instilled in the eye, only 10% of the active drug is absorbed into the eye, the remainder spills or enters the systemic circulation via the conjunctival vessels or the nasal mucosa via the nasolacrimal duct. Peak plasma concentration occurs within 30 minutes of instillation and can lead to systemic side effects, particularly in neonates. To limit systemic absorption, the lowest concentration of active ingredient should be used and the nasolacrimal duct occluded with a fingertip for a couple of minutes after drop instillation. Drugs used for diagnosis Topical anaesthetics Severe eye pain and blepharospasm can prevent adequate examination. Topical anaesthetics are helpful but should never be prescribed on a routine basis for analgesia, since corneal anaesthesia prevents epithelial healing and risks infection. Topical anaesthetics in common use are: • Proxymetacaine 0.5%: excellent choice for children, effect lasts 10 minutes, does not sting • Tetracaine 0.5%: longer-acting anaesthetic, useful for surgical procedures, severe stinging on instillation Fluorescein Fluorescein absorbs blue light and re-emits it in the green spectrum. It will light up areas of corneal and conjunctival epithelial loss if illuminated with blue light. It is available either as a Fluoret impregnated strip or eye drop. Refraction Anti-muscarinic drops block the parasympathetic innervation of the ciliary muscle and pupil sphincter, and are commonly used to allow accurate objective refraction in clinic. Side effects include stinging, blurred vision, photosensitivity, flushing and dry mouth. • Tropicamide 1%: onset in 15 minutes, lasts 3–6 hours • Cyclopentolate 0.5% (for infants) or 1%: onset in 20 minutes, lasts 24 hours • Atropine 1%: onset in 30 minutes, lasts 7 days Sympathomimetics are used synergistically with antimuscarinics for the intense mydriasis needed for intraocular surgery or ROP screening and treatment. Side effects include stinging, blurred vision, sensitivity to light. Rarely, tachycardia and hypertension can occur. • Phenylephrine 2.5%: onset in 20 minutes, lasts 12 hours Pharmacology and the eye The blood–ocular barrier prevents many systemic medications from reaching the intra-ocular tissues. Most chemotherapeutic agents cannot enter the eye, making it a sanctuary site for cancer, particularly acute lymphoblastic leukaemia. Absorption of topical therapy through the cornea is good and most anterior segment problems can be treated with drops (guttae – g)/ointment (oculentum – oc), with systemic therapy reserved for posterior segment disease. Many drops have preservatives which cannot be tolerated when applied intensively or when contact lenses are worn. The majority of commercial topical therapies are not licensed for use in children, but are regularly prescribed and have a historical safety record. Question 30.5 Ptosis at 6 months The parents of a 6-month-old infant are concerned about a unilateral partial ptosis, which has been present since birth. The baby was born at term after a complicated vaginal delivery. Your assessment shows no significant facial bruising, a 4 mm right ptosis with no evidence of anisocoria (unequal pupils) or strabismus. The child is otherwise developing well and there is no family history of note. What would be the most likely diagnosis? Select ONE answer only. A. Congenital dystrophy of the levator muscle B. Facial nerve palsy C. Forceps injury during birth D. Myasthenia gravis E. Partial third nerve palsy Answer 30.5 A. Congenital dystrophy of the levator muscle. Forceps delivery can result in Horner syndrome or a mechanical ptosis due to bruising, but there was no anisocoria or significant bruising in this case. Facial nerve palsy will cause lagophthalmos, not ptosis. Third nerve palsy would cause the eye to have a divergent squint. Neonatal myasthenia can cause ptosis but it is rare and usually bilateral. The most likely diagnosis is a congenital dystrophy of the levator muscle. This is a relatively common cause of ptosis and requires referral for amblyopia management and eventual surgery to improve the lid height.
30 606Ophthalmology available over the counter. Olopatadine is licensed for use in childhood allergic eye disease and stings less than others. Topical steroids are required for more severe types of allergy and uveitis but should only be started after an ophthalmological examination. High frequency topical steroid use can cause reduced plasma cortisol, steroid-induced glaucoma and risks ocular surface infection. Antibiotics and antivirals Bacterial conjunctivitis is extremely common and microbiological investigation is not required unless the conjunctivitis is chronic or occurring in the neonatal period. Although there are many different topical antibiotic preparations available, many are restricted to specialist use for treating infective keratitis and should be used after attempting culture of the affected site. The following topical antibiotics are suitable for use in a primary care setting: • Chloramphenicol (cheap, often used for postoperative prophylaxis, broad-spectrum agent) • Fusidic acid (cheap, good for staphylococcal infections) • Ofloxacin (useful first-line treatment if chlamydia is suspected) Topical antivirals such as aciclovir ointment are useful in herpes simplex keratitis but not effective in herpes zoster keratitis, which requires systemic treatment. Fortunately, fungal keratitis is extremely rare but it is devastating when it occurs. Candida keratitis can occur in immune-suppressed children and filamentous fungi (e.g. Aspergillus) can complicate trauma; amphotericin is the first-line topical antifungal. Drugs which can cause ocular toxicity Some systemic therapy can cause ocular toxicity. Children on the following drug treatments should have ophthalmic screening: • Ethambutol – optic neuropathy • Vigabatrin – retinal toxicity leading to visual field constriction • Hydroxychloroquine – causes maculopathy • Desferrioxamine – retinal toxicity • Amiodarone – corneal deposits and possible optic neuropathy Paediatric conditions which require ophthalmic screening Many childhood conditions are associated with ophthalmic problems. Sometimes the ophthalmic Investigation of pupil abnormalities Adie pupil Viral infection can disrupt the ciliary ganglion causing parasympathetic dysinnervation. Denervation hypersensitivity develops and can be clinically tested by using a diluted parasympathomimetic such as pilocarpine. This will have no effect on a normal pupil after 30 minutes, but a pupil with denervation hypersensitivity will become miosed. Horner pupil Interruption of sympathetic innervation to the eye decreases the concentration of noradrenaline (norepinephrine) around the synapse with the pupil sphincter. Cocaine drops prevent the re-uptake of noradrenaline at the synapse and will cause dilatation of a normal pupil within 30 minutes. The absence of noradrenaline around the synapse in Horner syndrome prevents pupillary dilatation. More recently, apraclonidine 1%, an alpha adrenergic receptor agonist which is routinely available in eye clinics, has been used to demonstrate denervation hypersensitivity of the pupil dilator muscle with Horner syndrome. A drop will cause a dilatation of the pupil in eyes with Horner syndrome and no appreciable difference in the normal eye after 30 minutes. Drugs used for glaucoma Improvement of aqueous outflow: • Parasympathomimetics modify the anatomy of the drainage angle by causing miosis: pilocarpine 1% • Alpha 2 adrenergic agonists: apraclonidine. Brimonidine is contraindicated for use in children since, unlike apraclonidine, it crosses the blood– brain barrier and causes cardiorespiratory depression. • Prostaglandin analogues: latanoprost, bimatoprost – these can darken iris colour and enhance eyelash growth Decreased aqueous production: • Topical beta blockers: timolol 0.1% or 0.25%. Side effects include bronchospasm, bradycardia, hypotension • Carbonic anhydrase inhibitors can be used topically or systemically: dorzolamide 2% or acetazolamide. Systemic use can commonly cause fatigue, depression, headache, paraesthesia and electrolyte disturbance. Drugs used for ocular inflammation and infection Allergic eye disease is usually treated with topical antihistamines and mast cell stabilizers, which are
607 CHAPTER THIRTY • Von Hippel–Lindau disease: annual screening for retinal angiomata • Post irradiation: screening for dry eye, cataract, radiation retinopathy • Neurofibromatosis type 1: screening for Lisch nodules and monitoring for visual pathway gliomas • Sickle cell/thalassaemia: screening for retinal ischaemia • Possible neurometabolic disease: corneal clouding, cataract, retinal dystrophy, cherry-red spot • Possible Wilson’s disease: screening for Kayser– Fleischer ring (copper deposition within the cornea) • Possible Alagille syndrome: screening for anterior segment anomalies (posterior embryotoxon), optic disc anomalies and retinal pigmentary changes • Possible Fabry disease: screening for corneal verticillata (whirl-like opacities in the cornea and retinal vascular tortuosity) Further reading Binenbaum G, Ying GS, Quinn GE, et al, the Premature Infants in Need of Transfusion Study Group. A clinical prediction model to stratify ROP risk using postnatal weight gain. Pediatrics 2011;127:607–17. Rahni JS, Cable N. Severe visual impairment and blindness in children in the UK. Lancet 2003;362:1359–65. Snell RS, Lemp MA. Clinical anatomy of the eye. 2nd ed. Malden, MA: Blackwell Science Inc; 1998. The Royal College of Ophthalmologists. UK retinopathy of prematurity guidelines. <http://www.rcophth.ac.uk/ page.asp?section=451>; 2008; [accessed 03.09.15]. The Royal College of Ophthalmologists. Abusive head trauma and the eye in infancy guidelines. <http:// www.rcophth.ac.uk/page.asp?section=451>; 2013 [accessed 03.09.15]. examination can help diagnostically, but for others screening and early treatment to prevent sightthreatening disease is important. Ophthalmic examination is required in the following settings: Neonate: • Prematurity: screening for ROP • Family history of early visual impairment: especially cataract, glaucoma, aniridia and retinoblastoma • Facial capillary malformation involving the eyelids: glaucoma screening Infant: • Syndromes/global developmental delay: ocular malformations, cataract, refractive error, cerebral visual impairment • Sensorineural hearing loss: screening for retinal dystrophy • Hydrocephalus: monitoring of optic nerve function • Potential non-accidental injury: screening for retinal haemorrhages • Incontinentia pigmenti: regular screening for retinal ischaemia and neovascularization Childhood: • Juvenile idiopathic arthritis: regular screening for chronic anterior uveitis • HLA B27-mediated arthropathy: screening for uveitis • Visual pathway tumours: monitoring of optic nerve function, visual fields • Diabetes: initial retinopathy screening 3–5 years after diagnosis, then annually • Marfan’s syndrome: screening for lens subluxation, myopia
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LEARNING OBJECTIVES By the end of this chapter the reader should: • Know the anatomy of the outer, middle and inner ear • Understand how the structure of the ear is related to function • Understand the process of hearing and how it may be impaired • Understand the process of ear development • Be aware of the genetic and environmental causes of hearing loss • Know how to investigate hearing loss • Understand about the assessment of hearing • Be aware of the treatment of hearing loss – medical management and use of hearing aids and cochlear implants 609 CHAPTER THIRTY-ONE Anatomy of the ear The ear is divided into the outer (external) ear, the middle ear and the inner ear. The outer ear consists of the auricle (pinna) and external auditory canal; the middle ear cavity is bordered by the tympanic membrane and contains the three ossicles; the inner ear (or labyrinth) consists of the cochlea (the organ of hearing) and the vestibular system (the organ of balance). The external ear Sound waves are collected by the pinna and channelled by the external auditory canal to the tympanic membrane, causing it to vibrate (Fig. 31.1). The shape and resonance of the pinna and external canal results in passive amplification of mid- and high-frequency sounds. Comparison of the inputs from both ears allows localization of the sound source. Children with unilateral hearing loss find it hard to localize sound or to understand speech in spatially separated background noise. The middle ear The middle ear is an air-filled cavity containing the malleus, incus and stapes. It transfers sound energy from air compression waves to pressure waves in the fluids of the cochlea. Normally, the loss of energy when sound waves in air hit a fluid medium is around 99.9%, equivalent to about 30dB, but the function of the middle ear is to offset this energy loss. The footplate of the malleus rests on the tympanic membrane, and detects vibrations from sound. This in turn is transmitted via the incus to the stapes, whose footplate rests on the oval window of the cochlea. The piston-like movement of the stapes footplate on the oval window sets up a travelling sound wave in the cochlear fluid (see below). The lever system of the ossicles and the difference in surface area of the large eardrum at one end, and the small stapes footplate at the other, means that sound is amplified more than twentyfold between the outer ear and the inner ear, offsetting the loss of energy between air and fluid. Kaukab Rajput, Maria Bitner-Glindzicz Hearing and balance C H A P T E R 31 Clinical relevance – conductive hearing loss When a child has a conductive hearing loss, either due to the presence of fluid in the middle ear, or because of congenital ossicular malformation or trauma, the hearing loss is likely to be around 30dB. It occurs predominantly in the low frequencies. Thus children with ‘glue ear’ can still hear speech as long as the speaker is close and clear.
31 610Hearing and balance The inner ear The cochlea The normal cochlea is a coiled structure with two and a half turns. It is divided lengthways into three fluid-filled compartments by two membranes, the basilar membrane and Reissner’s membrane. The scala tympani is the lower compartment, the cochlear duct (scala media) is the middle one and the scala vestibule is the upper compartment (Fig. 31.2). The scala vestibuli and the scala tympani are filled with perilymph, which has a composition similar to extracellular fluid, while the cochlear duct contains endolymph, which is unique, having a high potassium and low sodium concentration. The specialized sensory hair cells, responsible for converting sound energy into electrical impulses, and their supporting cells are known as the organ of Corti. The organ of Corti runs along the entire length of the basilar membrane. The vestibular system The vestibular part of the inner ear (labyrinth) is responsible for balance. It is divided into two functionally separate parts: the semicircular canals and the vestibule (Fig. 31.3). It contains an internal compartment (membranous labyrinth) containing endolymph which is surrounded by perilymph and these fluids are continuous with those of the cochlea. The membranous labyrinth is encased in bone. The three semicircular canals (SCCs) include the lateral (horizontal) canal, anterior (superior) canal and a posterior (inferior) canal, at approximately right angles to each other. The anterior and posterior canals detect rotation in the vertical planes (i.e. when the head is nodding or rolling), and the lateral canal detects horizontal movements (turning the head to the left or right). At the end of each semicircular canal is a dilatation called the ampulla, containing a patch of sensory hair cells called the cristae ampullares (see Balance and the vestibular system, below). The vestibule has two parts, containing the utricle and the saccule. These both contain an area (macula) of sensory hair cells. The areas are at right angles to each other and detect gravity and linear acceleration, such as when going up in a lift (vertical), or stopping and starting in a car at traffic lights (horizontal). Together, the utricle and saccule are called the otolith organs. The middle ear also contains two small muscles, the stapedius muscle, innervated by the facial nerve (VII) and the tensor tympani, innervated by a branch of the trigeminal nerve (V). These contract in response to loud sounds, reducing transmission of sound to the cochlea and protecting inner ear structures from damage. This response is known as the stapedial or acoustic reflex, and involves the VIIIth nerve, the brainstem nuclei and the VIIth nerve. Clinical measurements of the stapedial reflex can help to differentiate between certain types of hearing loss, and the possible location of the lesion. Connecting the middle ear to the nasopharynx is the Eustachian tube, which regulates the air pressure in the middle ear. Most of the time this is closed (collapsed), but swallowing, yawning and positive pressure may force it open transiently. Fig. 31.1 External, middle and inner ear. (From Levene M. MRCPCH Mastercourse, 2007, Elsevier Churchill Livingstone, with permission.) Outer ear Middle ear Inner ear Pinna Incus Malleus Ear canal Tympanic membrane Stapes Oval window Eustachian tube Semicircular canals (balance) Cochlea Auditory nerve (to the brain) Clinical relevance – external and middle ear abnormalities Abnormalities of the external and middle ears may result in conductive hearing loss. In children, Eustachian tube dysfunction is common, resulting in an increased tendency to otitis media with effusion (‘glue ear’). As the child grows, the Eustachian tube becomes more vertical in orientation and the problems generally resolve. Congenital abnormalities of the external or middle ears, such as external auditory canal atresia, or fixed or missing ossicles, cause conductive hearing loss.
611 CHAPTER THIRTY-ONE The organ of Corti consists of sensory cells (hair cells) and supporting cells. The hair cells are so called because they have hair-like, actin-filled projections on their apical surface, called stereocilia. There are three rows of outer hair cells and one row of inner hair cells. The stereocilia are arranged in rows of increasing height in a ‘W’ shape on the top of the outer hair cells, whereas the inner hair cells have a linear arrangement of stereocilia. The tallest stereocilia are embedded in an overlying gelatinous membrane, the tectorial membrane, and adjacent stereocilia of each hair cell are connected to each other by thin links, to form a hair bundle. The process of hearing: converting sound into electrical energy Inward movement of the stapes in response to sound transmitted through the middle ear produces deflection of the stereocilia towards the tallest row. This increases tension in the links between the tip and the side of the adjacent taller stereocilium. This causes physical opening of ion channels at the top of the stereocilia (like the pulling open of a trap door). Ions from the potassium and calcium-rich endolymph flow into the hair cells along an electrochemical gradient, causing depolarization of the hair cells. In turn, depolarization of the hair cells triggers the opening of voltage-gated calcium channels, and further influx of calcium. This increase in calcium concentration results in exocytosis of vesicles containing neurotransmitters at the base of the hair cell, increase in firing of afferent neurons, and transmission of impulses to the brain via the cochlear nerve. However, movement of stereocilia in the opposite direction Structure and function When the stapes footplate moves as a result of vibrations transmitted from the tympanic membrane, pressure waves in the cochlear fluid produce movement of the basilar membrane. On the basilar membrane is the organ of Corti (see Fig. 31.2), which detects this movement and converts it into electrical energy (auditory transduction). Fig. 31.2 Section through cochlea. ,QQHUKDLUFHOO 2XWHUKDLUFHOO 7XQQHOILEUHV 7XQQHORI&RUWL &RFKOHDU QHUYHILEUHV %DVLODU PHPEUDQH 7HFWRULDO PHPEUDQH 2UJDQRI&RUWL ,QQHUDQGRXWHU KDLUFHOOVDQG VXUURXQGLQJFHOOV 5HLVVQHU¶V PHPEUDQH 6WULDYDVFXODULV 6FDODYHVLEXOL SHULO\PSK 6FDODPHGLD HQGRO\PSK 6FDODW\PSDQL SHULO\PSK Fig. 31.3 The vestibular system. Anterior canal Lateral canal Posterior canal Vestibule Ampulla Saccule Cochlea Utricle Clinical relevance – the vestibular system The combination of input from the vestibular system, vision and proprioceptive information from the limbs and trunk allow the child to maintain posture and the ability to make movements (such as walking) without falling over. Therefore, a child with a structural malformation of the vestibular system, or impairment of its function, may well have delay in motor development, such as delayed head control, sitting and walking. As the child learns to use information from vision and proprioception, there is acquisition of these skills and compensation for vestibular failure.
31 612Hearing and balance its high potassium and low sodium concentration. The endolymph is also at a high positive potential (endocochlear potential). It is because of the electrochemical gradient between the endolymph and intracellular fluid that potassium flows into the hair cells when the channels at the top of the stereocilia are opened. Central projections Nerve impulses generated by sound are transmitted via the cochlear nerve with the vestibulocochlear (VIIIth) nerve to the cochlear nucleus, superior olive, inferior colliculus, medial geniculate body and up to the auditory cortex located in the temporal lobes. The auditory system is organized tonotopically, i.e. according to frequency (pitch) of the sound. This means that high frequencies are detected at the base of the cochlea and low frequencies at its apex, and this ‘tonotopicity’ is retained in most of the higher levels of the auditory pathways. The higher centres integrate peripheral inputs for functions such as localization and language processing. The latter is performed by association areas (primarily Broca’s and Wernicke’s areas), with the left side (receiving input from the right ear) dominant in most individuals. Balance and the vestibular system The sensory receptors of the vestibular system are in the ampullae of the semicircular canals (SCCs) and the otoliths (saccule and utricle). Similar to the cochlea, they contain hair cells, but with some important differences. The stereocilia connect to an overlying gelatinous structure called the cupula (similar to the tectorial membrane of the organ of Corti). Endolymph movement generated by head rotation pushes against the cupula, bending the hair cell stereocilia and thereby modulating excitation of the vestibular afferent fibres. The SCCs work in pairs so that when receptors in one ampulla are excited, those in the opposite ear are inhibited. Therefore, the afferent nervous output of each canal determines the magnitude of the rotation. Embryology The inner ear The inner ear begins to develop at about 3–4 weeks. In the caudal part of the hindbrain, there is a thickening of surface ectoderm to form the otic placode. The ectoderm then invaginates to form a cup and then the otic vesicle, or otocyst. The otic vesicle separates from the overlying ectoderm and starts to elongate to become the cochlear duct, with an appendage which is the endolymphatic duct and sac (Fig. 31.4). The Clinical relevance – genetic causes of deafness Genetic studies of children with congenital hearing impairment have shown that mutations in genes important for determining and maintaining the unique ionic composition of the endolymph are important causes of deafness in children. These include ion channels, transporters and gap junction proteins responsible for K+ recycling and maintenance of endocochlear potential. Mutations in the genes encoding these proteins may cause deafness in humans, with or without other clinical features. Genes include: • KCNQ1/KCNE1 (potassium channels) – causes deafness and long QT syndrome (Jervell and Lange-Nielsen syndrome) • SCL26A4 (a chloride/iodide transporter) which causes Pendred syndrome (deafness and goitre) • GJB2 (encoding the gap junction protein, connexin 26) – the commonest cause of genetic non-syndromic deafness in children Clinical relevance – disorders of hearing and vision The protein components of the tip links and other links between stereocilia (shaft connectors, top connectors and ankle links) are crucial for hearing. These proteins interact to form a series of large molecular complexes, which tether the stereocilia to each other and anchor the connectors to the central actin core of each stereocilium, providing rigidity. Mutations in the genes encoding these proteins give rise to non-syndromic as well as syndromic forms of deafness. Type 1 Usher syndrome, for example, causes deafness and retinal dystrophy. As the affected proteins are expressed in cochlear and vestibular hair cells, both parts of the inner ear are affected. These proteins are not only important for stereocilia formation and function, but are also expressed in the photoreceptors of the eye, hence the dual sensory pathology. The clinical presentation is frequently one of congenital profound hearing loss, so the infants fail newborn hearing screening and have gross motor delay such as poor head control, late sitting and walking due to absent vestibular function. Later in childhood, the children develop retinal degeneration starting with the rod cells, resulting in night blindness, loss of peripheral vision and eventual blindness. closes the channels. This causes hyperpolarization of the cell and reduction of firing. On the lateral wall of the endolymphatic (cochlear) duct is a specialized layered tissue called the stria vascularis. This produces the endolymphatic fluid, with
613 CHAPTER THIRTY-ONE second month, the auricles move laterally and upwards level with the eyes. Migration of neural crest cells into the first and second branchial arches give rise to muscles and ligaments, and of importance here, the ossicles. The first arch neural crest cells give rise to the malleus and incus, and the second arch cartilage to the stapes. cochlear duct continues to grow ventrally from the 4th–8th week and begins to coil. Within the cochlear duct, the organ of Corti begins to develop from cells in the wall of the duct. Mesenchyme surrounding the cochlear duct condenses and differentiates into the cartilaginous otic capsule. This later ossifies to form the bony labyrinth around week 23. Ganglion cells of the VIIIth nerve migrate into the cochlear duct and form the spiral ganglion, sending projections to the ends of the hair cells and the organ of Corti. The inner ear is fully developed by 20–22 weeks. The external and middle ear As the otic vesicle forms, the external and middle ear are also beginning their development just caudally. Development of the pinna of the external ear begins at about 5 weeks. It starts with the appearance of six mesenchymal swellings or hillocks, from the first and second branchial arches, surrounding the first branchial groove – from which develops the external auditory canal. Development begins in the upper part of the neck and as the mandible develops during the Fig. 31.4 Development of the inner ear. (From Moore KL, Persaud TVN, Torchia MG. Before we are born, 8th edition. Saunders 2013, with permission.) Otic placode Otic placode Otic pit Otic pit Otic placode Otic vesicle Otic vesicle Surface ectoderm Neural tube Developing hindbrain Surface ectoderm Mesenchyme Notochord Optic groove Neural fold Level of section B Level of section D Level of section F Site of optic vesicle C E G F D B A Clinical relevance – external ear anomalies Minor malformations of the external ear are not uncommon and may appear as isolated features or as part of a syndrome whose underlying mechanism is genetic. External ear anomalies range in severity from abnormal positioning, for example, low set or posteriorly rotated ears which reflect late developmental arrest of migration of the ears from their initial position in the neck, seen in Noonan’s syndrome, to severe microtia or external auditory canal atresia seen in conditions such as Treacher Collins syndrome.
31 614Hearing and balance Table 31.1 Some of the syndromes in which hearing loss is a major feature Syndrome Features Inheritance Importance Usher Hearing loss and retinal dystrophy Initially presents as NSHL. Child will have dual sensory impairment. Monitor for visual function. Jervell and Lange-Nielsen Congenital profound hearing loss with absent vestibular function; long QT interval with possible syncope AR Initially presents as NSHL. Assess QT interval; treat with beta blockers, or implantable defibrillator depending on cardiologist’s advice. Mortality is high if untreated. Pendred Progressive high-frequency hearing loss; vestibular function may be normal or affected; thyroid dyshormonogenesis; enlarged vestibular aqueducts and incomplete partitioning of cochlea AR Initially presents as NSHL. Assess for goitre and dyshormonogenesis; monitor for subsequent hypothyroidism. Treacher Collins Bilateral, symmetrical facial features; abnormal external ears often with meatal atresia; cleft palate; malar, zygomatic and mandibular hypoplasia; coloboma of lower eyelids and sparse lower eyelashes; ossicular abnormalities; sensorineural hearing loss AD Can range from mild to severe features, which may include airway obstruction and require tracheostomy; risk of gonadal mosaicism in unaffected parent. Waardenburg (WS) Pigmentary anomalies of hair, skin or eyes and hearing loss AD; also AR CHARGE Coloboma, Heart defects, Atresia of choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies (absent semicircular canals and VIIIth nerve hypoplasia) AD Clinical features highly variable; intellectual impairment may be mild to profound; development may initially appear to be severely delayed because of speech delay secondary to deafness and gross motor due to absent vestibular function. Alport High-frequency sensorineural hearing loss and nephritis XL; also AR; AD Intermittent haematuria (microscopic at first) leading to renal failure and characteristic findings on renal biopsy. AD, autosomal dominant; AR, autosomal recessive; NSHL, non-syndromic hearing loss; XL, X-linked. Clinical relevance – hearing loss at birth In the absence of a proven environmental factor, most hearing loss present at birth is likely to be genetic. An isolated case of congenital hearing loss, especially if severe or profound, has a high risk of recurrence because it is most likely to be autosomal recessive. If, after the detailed history and examination, the clinician feels it is still most likely that a child has a non-syndromic cause of hearing loss, the next investigation should be genetic testing and further investigation, particularly analysis of the GJB2 gene. Genetic causes of hearing loss Genetically determined hearing loss can either exist as an isolated feature (non-syndromic) or as a syndrome in which it is associated with other abnormal clinical features. It is said that around 70% of genetically determined childhood-onset hearing loss is nonsyndromic. Well over 100 genes are known to underlie non-syndromic hearing loss (NSHL) alone, and over 600 syndromes in which hearing loss is a feature have been described to date in the London Medical Databases (Dysmorphology and Neurogenetics) (see Further reading). Obviously, a paediatrician cannot be familiar with all of these syndromes, but some of the relatively common ones are listed in Table 31.1. It is helpful to be able to identify some of the more common syndromes involving hearing loss, to know how to approach investigation of a child with a suspected syndrome, and to be aware that some children who have apparent non-syndromic hearing loss may subsequently be determined as having a syndromic loss, as more clinical features become apparent with time. It is helpful to make these diagnoses in order to monitor for complications, and for the purposes of genetic counselling. For example, Pendred syndrome describes the association of congenital deafness and goitre, usually of teenage onset, which requires monitoring for subsequent hypothyroidism.
615 CHAPTER THIRTY-ONE subsequent pregnancy) and may reassure them that their child has a non-syndromic form of hearing loss. If the test for GJB2 mutations is normal, a child may still have a genetic hearing loss caused by any one of an increasing number of genes, but there may be very few phenotypic clues as to which gene may be responsible. However, until recently the number of genes causing non-syndromic hearing loss and their large size precluded further genetic investigation due to cost and manpower limitations. The advent of ‘next generation sequencing’ (NGS) allows large numbers of genes to be sequenced simultaneously at relatively low cost. Therefore, a significant proportion of children with hitherto unknown causes of hearing loss are likely to receive a molecular diagnosis in the future. Non-syndromic hearing loss is very heterogeneous and may follow any mode of inheritance. Most genetic hearing loss is inherited in an autosomal recessive manner, accounting for about 80% of cases. The implication of this is that there may be no family history of deafness, but the risk of recurrence is high at 1 in 4. The remaining cases are either dominantly inherited (around 10–15%) or X-linked or mitochondrial (5% combined). GJB2 is the commonest gene causing congenital deafness worldwide. It encodes the protein connexin 26. Connexins are components of gap junctions, present at the surface of epithelial cells to allow the passage of small molecules and ions between them. Gap junctions are thought to be essential for the recycling of potassium ions in the inner ear; potassium flows into hair cells from the endolymph when tip links cause the mechanotransduction channels at the top of the stereocilia to open in response to sound. This potassium has to be removed from the hair cells, and ultimately flows back to the stria vascularis, so that it can be transported into the endolymph again. GJB2 accounts for almost 50% of autosomal recessive causes in many diverse populations, i.e. where there are siblings affected or where the parents are related. Even in singleton cases where there is no family history, around 10–20% of children with profound congenital hearing loss will be shown to have homozygous or compound heterozygous mutations in this gene and so it has become a first-line investigation in a child with non-syndromic hearing loss. Identification of mutations in GJB2 helps to clarify genetic counselling for the parents (the chances of having another deaf child would be 1 in 4 with each Case history A full-term male infant was born to healthy unrelated parents, following an uneventful pregnancy and delivery. He failed his newborn hearing screen on day 2 and was discharged home and followed up in the audiology clinic. Repeat otoacoustic emission (OAE) testing could not detect emissions and the baby was referred for an automated brainstem response (ABR) test. Bilateral profound deafness was confirmed. Subsequent genetic testing of GJB2 revealed that he had homozygous truncating mutations in GJB2; both parents carried the common c.35delG mutation as well as a normal copy of the gene. Case history A baby was born at 32 weeks to healthy unrelated parents following reduced movements in utero. She required continuous positive airway pressure (CPAP) for 24 hours, and had a 48-hour course of penicillin and gentamicin, which was discontinued following lack of bacterial growth on cultures and clinical improvement. She was discharged home at 3 weeks but failed newborn hearing screening. Bilateral profound hearing loss was confirmed at 2 months. At the second and third tier clinic, the paediatrician noted the combination of deafness, bright blue eyes, hair between the eyebrows (synophrys) and widely spaced inner canthi of the eyes (dystopia canthorum) suggesting a possible diagnosis of Waardenburg syndrome type 1. This was subsequently confirmed by a de novo mutation in PAX3. Down’s syndrome Children with Down’s syndrome are prone to a number of complications causing hearing impairment, including glue ear, and this is managed with hearing aids rather than grommets. Conductive hearing loss can occur in up to 80%. An underlying SNHL occurs in a small percentage. Both the external auditory canals and the Eustachian tubes are narrower, and low muscle tone may also result in dysfunction opening and closing the Eustachian tubes. These factors tend to exacerbate and predispose to conductive and middle ear problems which persist for longer during childhood than in other children. Furthermore, their facial anatomy appears to result in greater prevalence of rhinitis and sinusitis. The impact of even mild hearing loss is probably more significant than in other children due to their other difficulties. Educational, language and emotional development may all be affected. Hearing and inspection of the ears and upper airways should be monitored.
31 616Hearing and balance the brain to look for signs of congenital CMV may be helpful. This is especially true where neonatal saliva or urine samples were not obtained. However, absence of clinical features cannot completely exclude CMV. In a child over 12 months of age, CMV IgG which is negative excludes CMV as a cause of deafness. Maternal CMV IgG is also useful and simple to test, which, when negative, excludes congenital CMV. Congenital rubella still occurs in unimmunized populations and causes SNHL, as well as visual problems, congenital heart defects and cognitive impairment. Congenital toxoplasmosis and congenital syphilis are also causes of SNHL and these conditions are treatable with antibiotics. These infections may be tested serologically. Widened/enlarged vestibular aqueducts Enlarged vestibular aqueducts are one of the most common malformations seen on imaging of the inner ear in those with sensorineural hearing loss. It is an important finding for several reasons; hearing loss may fluctuate although there may be sudden progression without restoration, especially after infection or minimal head trauma; balance may also be affected and there may sometimes be accompanying vestibular symptoms such as vomiting, nystagmus and unsteadiness. It is a frequent feature in Pendred syndrome. This finding should therefore prompt genetic/endocrine investigation and counselling about sudden deterioration in hearing following minor head trauma. Environmental causes Intrauterine infections There are a number of congenital infections that can cause congenital sensorineural hearing loss. Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of childhood SNHL, and is the commonest congenital infection worldwide (see Chapter 10, Perinatal medicine). The maternal infection is usually asymptomatic. There are abnormal clinical features in 10% of infected infants; the remaining 90% are asymptomatic at birth. SNHL affects approximately 50% of the survivors of the ‘symptomatic’ group, and 10–20% of the ‘asymptomatic’ group; these infants appear well, and are not routinely tested for CMV. Congenital CMV is the only treatable cause of childhood SNHL and is important to detect as early as possible, as antiviral therapy commenced in the neonatal period has been shown in a randomized controlled trial to prevent hearing deterioration and improve neurocognitive outcomes. For neonates with SNHL and congenital CMV, urgent referral to paediatric infectious diseases to discuss treatment options is advised. Antiviral therapy is currently given orally if the infant is otherwise well, and recent evidence supports 6 months of treatment. CMV-related hearing loss progressively worsens in half of cases. Bilateral profound deafness is the commonest audiological outcome, requiring referral for cochlear implantation. Congenital CMV also causes vestibular dysfunction and in a small proportion, visual problems. It is recommended that all children with SNHL of unknown aetiology should be offered tests for congenital CMV. In the neonate, PCR is used to detect CMV DNA in urine or saliva swab samples; presence of CMV DNA in urine or saliva in the first 3 weeks of life confirms congenital CMV infection. Testing of the newborn blood spot (Guthrie card) for CMV DNA and MRI of Answer 31.1 D. Ganciclovir treatment of infants with neonatally detected CMV-related hearing loss reduces the long-term sequelae. CMV DNA testing is only accurate in the first 3 weeks of life to identify congenital CMV. Cochlear implants are a successful treatment. The commonest specifically identified causes of congenital SNHL are genetic in origin. SNHL does not resolve spontaneously. Question 31.1 Neonatal hearing impairment A male infant is born at term, birth weight 3.5 kg. The pregnancy was uneventful and both he and his mother are clinically well. On his neonatal hearing screening test, he was noted to have bilateral sensorineural hearing loss (SNHL). His urine tested positive for CMV DNA. Which of the following statements is correct? Select ONE answer only. A. CMV DNA testing on saliva or urine can only confirm congenital CMV infection after 3 months of age. B. Cochlear implants are contraindicated in congenital CMV-related hearing loss. C. Congenital CMV SNHL is the commonest cause of failure to pass the neonatal hearing screening test. D. Ganciclovir treatment of infants with neonatally detected CMV-related hearing loss reduces the long-term sequelae. E. The hearing test should be repeated at 3 months as the hearing loss may have resolved spontaneously.
617 CHAPTER THIRTY-ONE on auditory function. Damage to the hair cells of the cochlea or to the stria vascularis is commonly associated with these therapeutic agents, and is thought to result from the production of free radicals that stimulate apoptosis in sensory cells and neurons causing permanent hearing loss. Some agents tend to be more vestibulotoxic if given in excess (e.g. gentamicin) and others more cochleotoxic (e.g. amikacin). Loop diuretics (such as furosemide) can potentiate the ototoxic effects of aminoglycosides. Co-treatment with salicylate has some attenuating effects on the ototoxicity of aminoglycosides in animals and humans, but there are currently no recommendations for such use of aspirin to counter the effects of auditory ototoxicity. Other antioxidants have shown promise in ameliorating the effects of cisplatin treatment. In some cases, mutations in the mitochondrial 12S ribosomal RNA specifically predispose vulnerable individuals to the side effects of aminoglycoside therapy even when drug levels are within normal therapeutic limits. The most common of these mutations is called m.1555A>G. This mutation increases the structural similarity of the mitochondrial ribosome to the bacterial ribosome and facilitates aminoglycoside binding. It occurs in 1 in 500 Caucasians and may be more common in other populations. However, the relationship of the mutation to aminoglycoside-induced ototoxicity is complex; some individuals appear to be exquisitely sensitive, and minimal doses precipitate irreversible deafness, yet others seem to be able to tolerate some aminoglycosides. This may be due to a Neonatal causes In the neonatal period, many factors can lead to increased risk of hearing loss in infants. Babies who are admitted to the neonatal intensive care unit have a tenfold increased risk of sensorineural hearing loss. Risk factors in preterm infants include low birth weight, hypoxia, exposure to noise and ototoxic drugs. Hyperbilirubinaemia is known to cause auditory nerve and cochlear damage, although deafness is transient in some cases. It is the toxic effects of circulating unconjugated bilirubin on developing neuronal pathways that can lead to bilirubin encephalopathy and kernicterus (see Chapter 11, Neonatal medicine). It is proposed that bilirubin disturbs the plasma, mitochondrial and endoplasmic reticulum membranes of neurons leading to the activation of cell death pathways. The severity of symptoms is dependent on the level of exposure and maturity of neural cells, and not just the peak total serum bilirubin measurement. Screening of hyperbilirubinaemic neonates using both ABR (automated brainstem responses) and OAEs (otoacoustic emissions) is recommended. Prenatal exposure of the fetus to high levels of alcohol can result in fetal alcohol spectrum disorder (FASD), including restricted growth, damage to the central nervous system and characteristic craniofacial anomalies. Although hearing loss is not generally recognized as a major component of FASD, some studies have reported an association with hearing loss. Drug ototoxicity Aminoglycoside antibiotics e.g. gentamicin and streptomycin, as well as platinum-based chemotherapeutic agents such as cisplatin, can have irreversible effects Case history A male infant was born at term with unilateral SNHL, detected by the newborn hearing screen, following a normal pregnancy. He was otherwise well, with normal findings on clinical examination. His urine tested positive for CMV DNA, as did his newborn blood spot, confirming congenital infection. He developed progressive hearing loss in his normally hearing ear by age one year. By age 2 years, his hearing loss had progressed bilaterally to profound loss. He had delayed speech and language, and impaired balance and gross motor skills for his age. During assessment for cochlear implantation his MRI brain revealed white matter changes in the anterior temporal lobes bilaterally, consistent with congenital CMV. He went on to receive cochlear implantation and make good progress. Case history Twins were born at 36 weeks following prolonged rupture of membranes. Pregnancy had been normal until then. Twin 1 weighed 2.1 kg, and twin 2 weighed 1.98 kg. Both were given 3 days of benzyl penicillin and gentamicin. The babies were well but remained in the special care baby unit for 2 weeks to establish feeding. At aged 4 years, on the school entry screen, twin 2 was referred to local audiology services because hearing loss was suspected. Pure tone audiometry showed a mild to moderate high-frequency hearing loss, worse on the right side. In view of the history of progressive hearing loss and aminoglycoside exposure, he was later tested for m.1555A>G which showed the mutation to be present. The mutation was also present in twin 1, who on testing had a mild to moderate hearing loss at 8 kHz. Their mother was shown to have normal hearing as were three older siblings. The presence of m.1555A>G mutation may have made him more susceptible to aminoglycoside-induced ototoxicity.
31 618Hearing and balance Malignancy Tumours of the brain and ear and leukaemia can present with hearing loss, imbalance and may be associated with headache and raised intracranial pressure, abnormal eye movements and cranial nerve lesions. Trauma Traumatic hearing loss can be due to surgical trauma, head injury, or exposure to very loud noise. Auditory neuropathy or auditory dyssynchrony Sensorineural hearing loss caused by auditory neuropathy (AN) or auditory dyssynchrony (AD) represents 7–10% of hearing loss and is characterized by normal transient-evoked otoacoustic emissions (OAEs) or cochlear microphonics (CM) but abnormal automated auditory brainstem responses (AABRs). In 75% of affected children, the underlying pathophysiology is dysfunction of inner hair cells while outer hair cells remain active. In these cases, cochlear implantation generally works well when hearing aids have failed to improve auditory development. Investigating the cause of infant and childhood auditory neuropathy (i.e. normal OAEs with abnormal ABR with cochlear microphonics) is essential, as it is increasingly reported that in some cases, particularly at-risk neonates, this condition may resolve over time. Regular testing after the age of 6 months and up to at least 12 months of age is recommended, and it is considered particularly important to obtain a behavioural measure of auditory response before proceeding with cochlear implantation surgery. If the cause of AD/AN SNHL is unknown, a viable approach may be to watch and wait; the hearing loss may be transient, and performing cochlear implantation may destroy any potential residual hearing. Other causes of AN/AD include abnormalities of the afferent neural synapse, cochlear nerve, cochlear nucleus, auditory brainstem tracts and central auditory system, which are more difficult to overcome with cochlear devices. Further tests, including MRI and specialized physiological testing, can assist in the identification of individual pathologies. Low-birth-weight infants are at increased risk of AN/AD, and onset correlates with exposure to ototoxic antibiotics, dexamethasone, hyperbilirubinaemia, hypoxia, ischaemia, immaturity of the central nervous system or mechanical ventilation. Other aetiological factors include intrauterine infections, complex syndromal disease, and non-syndromic forms of genetic hearing loss. threshold below which deafness is not an inevitable sequel, or additional genetic modifiers which protect against ototoxicity. Further epidemiological studies are needed to determine the actual burden of this type of hearing loss to deafness, particularly in premature or sick neonates in whom aminoglycosides form part of first-line recommended antibiotic therapy. Meningitis and other infections SNHL occurs in 26% of survivors of pneumococcal meningitis and in about 11% following meningococcal meningitis. Bacterial invasion of the perilymphatic spaces in the cochlea can result in severe suppurative labyrinthitis, and it is thought that the subsequent production of reactive oxygen and nitrogen species leads to the damage and death of hair cells and spiral ganglion neurons. Within a few months of infection, new bone formation (ossification) occurs in the semicircular canal and extends to the scala tympani in the basal turn of the cochlea, which can complicate, but does not preclude, partial cochlear implant surgery. More extensive brain damage that can occur during meningitis infection may affect central auditory processing with subsequent consequences for outcome. Mumps and measles are preventable causes of SNHL, but are less of a problem since the introduction of the MMR vaccine. Bacterial infection of the air spaces within the mastoid bone, ‘mastoiditis’, as a result of persistent middle ear infection may also cause hearing loss, although rapid treatment with antibiotics is effective and this is now uncommon in developed countries. Case history A 12-year-old girl who has bilateral moderate– severe hearing loss following meningococcal meningitis at the age of 8 years is referred regarding dizziness on head movement. Vestibular function testing confirmed bilateral vestibular hypofunction and she was referred for vestibular physiotherapy. Autoimmune conditions Autoimmune conditions can lead to acquired or lateonset hearing loss, which can be of sudden onset or progressive and is often associated with dizziness and sometimes tinnitus. It may also lead to cochlear ossification, and urgent scanning and cochlear implantation may be required in a rapidly progressing autoimmune-mediated hearing loss.
619 CHAPTER THIRTY-ONE If there is no obvious syndrome apparent, some basic investigations should be performed in all children with hearing loss of unknown cause (Fig. 31.5). The consequences and measurement of hearing loss Functional consequences of hearing loss Hearing is important for awareness of many environmental sounds, but assessment usually focuses on the ability to hear speech as this has a major impact on language development and social functioning. If a child is unable to detect the spoken voice, there is no potential for acquisition of normal speech and language, with obvious far-reaching consequences. Lack of access to language, be it spoken or manual, such as sign language, will result in communication difficulties (depending on the severity of the hearing loss), with consequential educational and psycho-social Fig. 31.5 Simple algorithm for investigation of congenital/ childhood hearing loss. Radiological investigation should include MRI of the internal auditory meati (IAMs) and brain and renal ultrasound, especially if there are external ear anomalies. CT scanning should be carried out if there is a mixed hearing loss. EVA, enlarged vestibular aqueduct; NGS, next generation (massive parallel) sequencing. Presentation Syndromic Recognizable or not? History (family history) Define features Eye exam Search database Request investigations ‘Non-syndromic’ Is the balance normal? Normal ECG, ERG Abnormal Define syndrome e.g. Pendred, EVA, X-linked CMV, Urine dipstix Family audiograms Ophthalmology Radiology CMV, GJB2 then gene panel NGS No Yes Syndrome e.g. Usher, JLNS Non-syndromic Gene panel, NGS Question 31.2 Glue ear A 3-year-old boy attends outpatients with a history of recurrent episodes of otitis media. Otoscopic examination reveals fluid behind both tympanic membranes. A diagnosis of bilateral glue ear is made. Which of the following best describes the hearing loss associated with this condition? Select ONE answer only. A. Conductive hearing loss at all frequencies B. Conductive hearing loss of 30dB at high frequencies C. Conductive hearing loss of 30dB at low frequencies D. Conductive hearing loss of 30dB at mid frequencies E. Sensorineural hearing loss at all frequencies Investigation of hearing loss Answer 31.2 C. Conductive hearing loss of 30 dB at low frequencies. In the case of a child with congenital or significant sensorineural hearing loss, the first diagnostic clues as to whether the cause is genetic or environmental, and if there is associated developmental delay, will come from history and clinical examination. Motor delay may suggest a vestibular problem if it is unaccompanied by delay in other domains. Immunization history is required with regard to MMR vaccination, as mumps, rubella and measles all cause hearing loss. Questions should also include family history of hearing loss and features of common syndromes (renal disease, eye diseases, pigmentary anomalies, thyroid disorders); consanguinity makes recessive inheritance more likely. Examination should include looking at the overall appearance of the child and then at specific features in detail: the shape, spacing, colour and orientation of the eyes and eyebrows; the shape and position of the ears, looking especially for pits and tags (suggestive of branchio-oto-renal syndrome (BOR) or Treacher Collins syndrome); the neck in terms of fistulae or marks (branchio-oto-renal syndrome), and shape (Noonan’s syndrome); the skin in terms of texture, pigmentation, birth marks; the mouth, to look at the teeth in an older child and the shape of the palate, as well as the fingers and toes.
31 620Hearing and balance Rather, it is a ratio and is used to define a sound level as compared to a reference sound pressure. Two dB scales are used in hearing assessment: • dB HL (hearing level) is the scale used for most threshold measurements. Audiometers and most other hearing measurement devices display levels in dB HL. With this scale, the reference pressure is that of normal hearing thresholds at each frequency (so that ‘normal’ thresholds are 0dB HL). However, there is some variation, so that some individuals have slightly better thresholds (such as −5dB HL) and thresholds up to 20dB HL are usually considered to be in the normal range. • dB A is an alternative scale, which is often used by sound level meters to measure sounds in the ‘free field’, especially when discrete frequencies are not being measured, such as speech sounds or background noise (Fig. 31.6). Audiometry is the process of measuring hearing thresholds at a range of frequencies (pitches). problems. Late-onset and progressive hearing loss in older children will similarly hamper further educational progress and life opportunities without appropriate audiological rehabilitation. As outlined above, there is a wide range of aetiologies that produce hearing loss of varying degrees of severity. An important distinction in the assessment process is between permanent sensorineural losses (involving the cochlea) and conductive (middle ear) losses, which are usually temporary. Most types of hearing loss can be ameliorated by hearing aids or other devices to some degree (see below). Assessment of hearing loss The usual way to assess hearing function is to measure auditory thresholds, i.e. the quietest sounds which can be detected, as most hearing problems are associated with raised (poorer) thresholds. The unit of measurement for sound levels is the dB (decibel), but the dB in isolation has no real meaning. Fig. 31.6 Frequency and loudness of some everyday sounds. (From Levene M. MRCPCH Mastercourse, 2007, Elsevier Churchill Livingstone, with permission.) mdb n ng el u k phg fsth chsh i ar Hearing level in decibels (dB) -10 0 10 20 30 40 50 60 70 80 90 100 120 125 250 500 1000 2000 4000 8000 110 Frequency in hertz (Hz) Low High zv j o
621 CHAPTER THIRTY-ONE Thresholds may be measured in various ways and are usually displayed on an audiogram, which shows the thresholds at each audiometric frequency. Figure 31.7 shows several audiograms. The horizontal axis shows the test frequencies. Octave intervals are tested from 250 to 8000 Hz (8kHz). The vertical axis is the level of sound (dB HL) where the quietest levels are at the top. Thus, the ‘normal range’ is anything down to 20dB HL and thresholds higher than 20dB HL (lower on the audiogram) represent a clinically significant hearing loss. Thresholds for different degrees of hearing loss are as follows: • Normal hearing: less than 25dB in adults and 15dB in children • Mild hearing loss: 25–39dB. • Moderate hearing loss: 40–69dB. • Severe hearing loss: 70–94dB. • Profound hearing loss: 95+dB Functional hearing is represented by ‘air conduction’ (AC) thresholds (as shown in Figure 31.7), ideally measured using headphones, but often ‘bone conduction’ (BC) thresholds are also measured using a vibration generator placed on the mastoid bone. The national Newborn Hearing Screening Programme Currently, all children in the UK are screened shortly after birth under the national Newborn Hearing Screening Programme (NHSP). This is coordinated by regional audiological services and most babies are tested on maternity units within 48 hours of birth. Often, mothers are discharged prior to screening, in which case the tests are performed at home visits. Otoacoustic emissions (OAEs) are sounds generated by the outer hair cells of the inner ear in response to an auditory stimulus. They are conducted through the middle ear and can be detected in the ear canal. Detection indicates a high degree of normality in the functioning of the middle ear and inner ear and is therefore a good screening test. However, it cannot detect all causes of hearing loss since the signals picked up by the cochlea also need to be transmitted higher up the auditory pathways. All babies receive a test of OAEs shortly after birth. During testing, a soft probe is placed into the ear canal and the OAE or ‘cochlear echo’ is recorded in response to moderate level sound clicks delivered via the same probe. Presence of an OAE response (screen ‘pass’) confirms normal or near-normal hearing. Absence of a response indicates the possibility of a hearing loss and the need for follow-up testing, though is often due to temporary factors, such as excessive head movement or middle ear fluid. The main follow-up test is auditory brainstem response (ABR) testing, which can detect retrocochlear pathology (Fig. 31.8). Disposable electrodes are attached to the baby’s head and rapid clicks or tone pips are delivered to the ear by an insert probe. The electrodes detect field potentials generated by the lower auditory pathways (cochlea and brainstem), producing a characteristic waveform response. The intensity of the stimuli are reduced until the waves are no longer visible, providing a close approximation to behavioural hearing thresholds. Note is taken of the amplitude (reflecting the number of neurons firing), latency (the speed at which the waves are transmitted), interpeak latency and interaural latency (the difference between ears in terms of wave V latency). Babies demonstrating raised thresholds are monitored by audiological services and sometimes provided with hearing aids immediately if there is a large hearing loss. Babies with certain risk factors (e.g. a graduate from the neonatal intensive care unit) are tested using both OAE and an automated version of the ABR test (AABR). One of the main aims of this combination is to identify auditory neuropathy spectrum disorder (ANSD), as this usually results in normal OAE but poor/absent AABR responses. OAE is quick and easily administered, and is highly acceptable to parents to perform. About 15% of infants screened by OAE will be referred for further testing by ABR. Around 3% will subsequently be referred for formal audiology assessment. About 1 in 10 to 1 in 15 of infants referred on for detailed audiometry will be found to have a significant hearing problem. Overall, the NHS Newborn Hearing Screening Programme (see Box 2.12) identifies 1–2 per 1000 babies born in the UK as having hearing loss affecting one or both ears (1.1 per 1000 bilateral; 0.6 per 1000 unilateral). Behavioural threshold testing in older children Older children are usually assessed using behavioural tests of hearing, as these are considered to represent functional hearing more reliably than objective tests. From around 6 months to 3 years of age, the usual method is visual reinforcement audiometry (VRA). The child sits in front of a low table and one of the testers keeps the child’s attention to the front using simple toys. To one side is a loudspeaker and a visual reinforcer (a box containing an interesting toy). During the initial (conditioning) phase, moderately loud sounds are delivered for a few seconds and the reinforcer is illuminated and/or activated. The
31 622Hearing and balance Fig. 31.7 Audiogram showing normal, conductive, sensorineural and mixed hearing loss. (From Levene M. MRCPCH Mastercourse, 2007, Elsevier Churchill Livingstone, with permission.) Air conduction to R ear Air conduction to L ear Bone conduction (not masked) Conductive hearing loss is present if bone conduction thresholds are normal but air conduction thresholds are raised Sensorineural hearing loss exists when the bone conduction and air conduction thresholds are raised Mixed hearing loss occurs when there is conductive overlay (an additional air-borne gap) on top of an existing sensorineural hearing loss Mixed hearing loss in the right ear (pure sensorineural on left) Bilateral sensorineural hearing loss Conductive hearing loss Normal hearing -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 125 250 1000500 2000 4000 8000 Frequency (Hz) Hearing level (dB) R L
623 CHAPTER THIRTY-ONE though it is often possible to measure ear-specific BC thresholds by ‘masking’ the opposite ear. Auditory processing tests Some children can have difficulties in understanding speech even though their auditory thresholds appear to be normal. Such cases may be due to auditory processing disorder (APD). Specialized tests are available to assess central processing, which include components such as auditory memory (digit span) and competing speech (where target words or phrases presented to one ear are repeated by the child while competing speech is presented to the opposite side). Results are compared to age-specific norms (typically for ages of around 7–12 years). Tympanometry Temporary middle ear congestion is common in young children and can produce a conductive hearing loss which increases thresholds by up to 30–40dB. Tympanometry is therefore usually performed as part of a hearing assessment, which is a physical measurement not requiring any patient response. A probe is placed in the ear canal for a few seconds, which delivers a tone and changes the air pressure. The way in which the pressure changes affect the sound level developed in the ear canal provides information about the status of the middle ear (Fig. 31.9). reinforcer is pointed out to the child so that he/she learns to associate the sound with the reinforcer activation (reward). During the test phase, the child’s attention is kept forward and tones are occasionally delivered via the loudspeaker without reinforcer activation. If the child turns to look at the reinforcer, then it is activated (to maintain conditioning) and the response is taken to indicate positive hearing. The sound level is reduced until the child does not respond, so that the threshold for that frequency can be estimated. Several frequencies are usually tested, but the thresholds obtained relate to the ‘better’ ear, i.e. a child may not hear on one side but still be able to respond normally using the good ear. VRA is therefore sometimes performed with the sounds delivered by insert phones rather than a loudspeaker, in which case ear-specific thresholds can be measured. Pure tone audiometry (PTA) is considered the ideal behavioural hearing test because it depends on active listening. Headphones are used to deliver short tones at individual frequencies. Older children are required to press a button each time the tone is heard, but the test may be modified in younger children (‘play audiometry’), where the response will involve actions with toys. The level of each tone is adjusted to identify thresholds. Children as young as 21 2 years can usually be tested using some form of PTA. To differentiate between conductive and sensorineural hearing losses, visual reinforcement audiometry (VRA) and pure tone audiometry (PTA) can also be used to measure bone conduction (BC) thresholds using a bone vibrator in place of loudspeaker or headphones. The vibrator is held over the mastoid bone by a flexible band and by-passes the middle ear, indicating the status of the cochlea. The skull vibrations pass to both ears more or less equally, and so measured thresholds actually represent the better ear, Fig. 31.8 Schematic representation of the auditory brainstem response (ABR). The output consists of five waves; waves I to III are generated by the auditory branch of the VIIIth nerve, the spiral ganglion and the cochlear nucleus (lower brainstem), and waves IV and V by the upper brainstem (superior olivary complex and inferior colliculus). (VIII N) I (VIII N) II (CN) III (SOC) IV (LL & IC) V Fig. 31.9 Example tympanogram shapes (according to the so-called ‘Jerger classification’). The peak of each curve indicates the amount of tympanic membrane (TM) movement, which normally occurs at around normal (0 daPa) middle ear pressure (as in A). The other curves are abnormal: As shows a flattened peak (reduced ‘compliance’) at normal pressure, indicative of early or resolving middle ear effusion; Ad shows abnormally high compliance typical of ossicular dislocation; B is a flat trace, seen with severe effusion or perforation; the C trace shows normal TM movement but negative middle ear pressure (i.e. TM retraction). –400 0 A C B Ad As 1 Acoustic compliance (cm3 eq. vol ) –200 Middle ear pressure (daPa) 0 200
31 624Hearing and balance very effective as the cochlea is usually normal, but there may be other practical difficulties. Parents need guidance in order to ensure that their child benefits from aiding, and practical difficulties may largely offset potential benefits. Another problem is that OME often produces hearing losses that fluctuate in severity over time, so that a child using hearing aids may be under- or over-amplified at different times. Permanent conductive losses Craniofacial abnormalities involving the outer and/or middle ear often produce permanent conductive hearing losses. There may be a deformed or absent pinna, absent external auditory meatus or ossicular or other middle ear abnormalities. The resultant hearing loss will be permanent, stable and may be severe (up to around 60dB), particularly if there is an absent auditory meatus. The cochlea is usually (but not always) normal or near-normal. Reconstructive surgery is rarely effective in addressing these hearing losses, but may be of significant benefit for cosmetic purposes, particularly if the pinna is severely affected. Hearing loss is therefore usually managed using various types of hearing aids. Conventional ‘air conduction’ aids may be used in some cases, but more often bone conduction aids are required in order to by-pass the conductive loss. These may be body-worn or ear level, but with a bone vibrator placed on the mastoid bone instead of sound output to the ear canal. The acoustic signal provided by these aids is generally good, but there are significant practical difficulties in keeping the vibrator in place, especially in a young child, and the headbands can be uncomfortable. In recent years, there has been a large increase in the use of bone-anchored hearing aids (BAHAs). These use a titanium fixture surgically-implanted into the mastoid bone. An external processor (similar to a hearing aid) picks up external sounds and vibrates the implanted fixture. The vibrations pass through the skull very effectively to stimulate the cochlea (on both sides) in a similar manner to measurements of bone conduction thresholds in audiometry. There are several types of commercially available BAHA, of two fundamental designs. Some use a ‘percutaneous’ abutment, which protrudes a few millimetres through the skin. The external processor is directly connected to the abutment and can be coupled or removed as required. The alternative design is ‘transcutaneous’, in which the external processor produces vibration of an implanted magnet by electromagnetic induction across the intact skin (Fig. 31.10). Transcutaneous systems are often favoured for cosmetic and infection control reasons, but they cannot address sensorineural elements of a hearing loss as effectively as Treatment of hearing loss Conductive hearing losses Temporary conductive losses Temporary conductive hearing loss due to middle ear congestion (otitis media with effusion; OME) is very common in children, particularly in the pre-school years and with certain conditions such as Down’s syndrome. There may be tympanic membrane retraction, middle ear fluid and sometimes perforations if fluid has become infected. All of these produce some degree of conductive hearing loss. Typically, this will be in the order of 20–40dB, and tends to be predominantly in the low frequencies. The hearing loss may be unilateral, but both ears are often affected at similar times. Such hearing losses do not usually have a major functional impact, at least in the short term. Parental speech is usually audible as long as the parent is reasonably close. School-aged children tend to be affected more severely than younger children, as they often have to cope with high levels of classroom noise as well as more distant speakers. As OME usually resolves within days or weeks, the first-line of treatment is to monitor the situation, with parental advice to keep the voice full and clear (but without shouting) and with awareness of the effects of speaker distance and background noise. Medical intervention would not usually be considered until the condition has persisted for several months with documented significant hearing loss. Although a formal hearing test would usually be performed at some point, particularly before intervention is considered, the disease status can often be satisfactorily monitored by tympanometry alone, typically performed every month or so. If the condition is bilateral and persists for many months, then surgical intervention may be considered, though this strategy is not universal. The condition often recurs after initially successful intervention, so that some ENT clinicians feel that intervention is not always justified. Surgical intervention usually involves myringotomy (small incision in the tympanic membrane) under general anaesthetic, aspiration of middle ear fluid and insertion of a grommet, which maintains aeration of the middle ear. Grommets usually extrude naturally after several months, by which time the cause of the problem (usually inflammation of the Eustachian tube) has resolved, though specially designed ventilation tubes are available if longer term treatment is required. Occasionally, hearing aids (covered in more detail below) may be prescribed if there is a longstanding hearing loss, though, again, this practice is not universal. Amplification of conductive hearing loss is usually
625 CHAPTER THIRTY-ONE usually includes audiovestibular physicians, teachers of the deaf, speech and language therapists, ENT, and sometimes educational psychologists. Cochlear implants Sometimes a hearing loss is very severe or profound and conventional hearing aids are not able to provide sufficient amplification for speech understanding. In this situation, a cochlear implant (CI) may be considered, which effectively substitutes for the defective transduction of sound into neural signals that is normally achieved by the cochlear hair cells. If there is extensive inner hair cell damage, then an acoustic signal is unable to provide a satisfactory auditory percept, no matter how much amplification is provided. The fundamental role of the CI is therefore to stimulate the peripheral neural elements electrically. Following inner hair cell loss, the primary afferent axons often degenerate, but many of the spiral ganglion cell bodies (together with their central projections) survive and these provide the main target neural elements for electrical stimulation. There are several commercially available CIs, but they all have a basic layout, as illustrated in Figure 31.11. An external ear-level processor (inset) picks up sounds from the environment, processes them and passes the signal to an external transmitter coil. The transmitter sends a coded signal, together with electromagnetic power, through intact skin, to a surgically implanted receiver embedded in the mastoid bone. The receiver decodes the signal to produce a sequence of rapid electrical pulses, which are delivered to a row (array) of electrodes inserted into the scala tympani of the cochlea via the round window. The incoming sound signal is divided into frequency bands, with low-frequency signals ultimately delivered to the most apical (deepest) of the implanted electrodes and high frequencies to the basal end of the percutaneous systems. In general, BAHAs are more acceptable than headband BC devices and provide a superior sound quality. They are also often used in cases of chronically discharging middle ears, as these may be exacerbated by the use of air conduction aids, which occlude the ear canal. Sensorineural hearing loss Sensorineural hearing losses may be of any severity or audiometric configuration, though severe and profound losses tend to be more pronounced in the high frequencies. They are almost always permanent but sometimes deteriorate further over time. In children, the majority of sensorineural losses are congenital or linked to neonatal factors, and nowadays most are identified through the Newborn Hearing Screening Programme. Any pre-lingual bilateral hearing loss of moderate degree or greater will potentially affect language acquisition in the early years, so that early intervention is of vital importance. Apart from various types of short-term medication for certain specific conditions, such as antiviral therapy for congenital CMV, there are currently no medical or surgical treatments that can reverse sensorineural hearing loss, so the primary treatment is provision of hearing aids. Hearing aid provision is managed by hospital audiology departments, who review children on a regular basis and usually provide open access for repairs and production of new ear moulds. Modern digital aids are computer-programmed in order to adjust their output to match the type and severity of the hearing loss. Some also have advanced sound processing features, such as directional microphones and noise reduction algorithms, and they may be compatible with external devices such as FM systems (see below). All school-aged and most pre-school children also receive support from a multi-disciplinary team, which Fig. 31.10 Bone-anchored hearing aids showing the mode of action of a percutaneous device. The external processor vibrates the implanted fixture by direct coupling via the abutment and vibrations pass to the cochlea through the bone. BAHA Fig. 31.11 Diagram of a cochlear implant. External magnet – outside the skin External transmitter antenna – outside the skin Internal magnet, antenna and receiver stimulator – under skin Electrode Microphone Processor/ battery
31 626Hearing and balance Summary There are about 45,000 hearing-impaired children in the UK. Hearing loss in children may be due to genetic or environmental factors. Aetiological investigation is important for both management and counselling parents. Prompt evaluation and rehabilitation is vital in order to minimize the effect on the child’s language and social development. Further reading Ardle BM, Bitner-Glindzicz M. Investigation of the child with permanent hearing impairment. Arch Dis Child Educ Pract Ed 2010;95(1):14–23. Bonnet C, El-Amraoui A. Usher syndrome (sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches. Curr Opin Neurol 2012;25(1):42–9. British Association of Audiovestibular Physicians. Documents, guidelines and clinical standards. <http://www.baap.org.uk/ Resources/Documents,GuidelinesClinicalStandards.aspx>; 2015 [accessed 04.09.15]. Chan DK, Chang KW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 2014;124(2):E34–53. Hereditary Hearing Loss Homepage. <http:// hereditaryhearingloss.org>; [accessed 04.09.15]. An updated series of webpages detailing known genes and loci for hearing loss with links to Pubmed. London Medical Databases. <http://www.lmdatabases.com>; [accessed 04.09.15]. McCormick B, editor. Paediatric audiology 0–5 years. London: Whurr; 2004. Norrix LW, Velenovsky DS. Auditory neuropathy spectrum disorder (ANSD): a review. J Speech Lang Hear Res 2014;57(4):1564–76. Oliver SE, Cloud GA, Sánchez PJ, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46(Suppl. 4):S22–6. Public Health England. NHS newborn hearing screening programme (NHSP). <https://www.gov.uk/topic/ population-screening-programmes/newborn-hearing>; 2015; [accessed 04.09.15]. Toriello HV, Smith SD. Hereditary hearing loss and its syndromes. Oxford Monographs on Medical Genetics. Oxford: Oxford University Press; 2014. cochlea, thereby maintaining its normal tonotopicity. The amplitude of the rapid stimulating current pulses is modulated in order to represent loudness changes over time within each frequency ‘channel’. Auditory thresholds using a CI are typically around 20–25dB HL, so that all but the quietest speech sounds are audible. A CI does not restore normal hearing; most adults describe the percept as ‘robotic’, but many recipients are able to follow speech without lip-reading except in very noisy conditions. Children with profound congenital hearing losses who receive CIs at an early age (typically between 12 and 24 months) usually develop near-normal speech and language and are able to attend mainstream schools. Provision of CIs in children is through about 20 dedicated centres in the UK, which receive most referrals through tertiary ENT and audiological services. Referral criteria are based on NICE guidelines. Auditory brainstem implants In very rare instances, there is gross abnormality of cochlea, absent cochlea, or absent cochlear nerve. Auditory brainstem implant can be considered but is not widely available. Assistive listening devices In addition to hearing aids or CIs, many children with significant hearing loss are often provided with assistive listening devices (ALDs), which may be supplied by social and/or educational services. There are a variety of devices, such as doorbell and telephone amplifiers, and devices providing an interface between phones, televisions, etc., and hearing aids (via direct input). The most important ALDs in educational settings are personal FM (frequency modulation) systems, consisting of a transmitter worn by the teacher and a receiver worn by the child, which uses the direct input option of the hearing aid or CI processor. FM systems are very effective in reducing the deleterious effects of classroom noise.
LEARNING OBJECTIVES By the end of this chapter the reader should: • Know about the epidemiology of adolescent medicine • Know about the physical and psychological changes during adolescence • Know about the mode of action and physiological consequences of substances taken without medical advice for recreational use • Be aware of chronic pain in adolescence and its management • Understand the main issues relating to sexual health • Be aware of the issues around the transition of young people to adult services 627 CHAPTER THIRTY-TWO Adolescent healthcare has come a long way since Amelia E Gates, a San Francisco physician, established the first dedicated adolescent clinic at Stanford in 1918. However, a century later, the healthcare provision for young people is still in major need of improvement (see Chief Medical Officer’s report, 2012). Although it has been included as a separate chapter, there are important strands of adolescent medicine woven through many of the other chapters. What is adolescence? Adolescence is the transition from childhood to adulthood. It is a complex sequence of profound biological, psychological and sociological changes, which can have a significant impact on a young person’s health and behaviour. Perhaps because of their proximity to adulthood, it is frequently forgotten that young people are at a genuine developmental stage with specific needs just like children at other ages. They are not yet adults, but neither are they children. This needs to be considered when trying to understand their behaviours and specific health requirements. It is facilitated by adopting a life-course approach to healthcare where adolescence is seen as integral in the continuum between childhood and adulthood. Defining adolescence according to specific ages is problematic because, as in other aspects of child development, there is much variation in both timing and tempo between individuals (Box 32.1). Throughout this chapter, the WHO definition of adolescence of 10–19 years will be used. The start of adolescence reflects the onset of puberty and begins earlier in girls with breast budding, normally at 10–11 years. Defining an end to adolescence is more complex, although the provision in law of minimum age limits is implicit of society’s expectation that sufficient neurodevelopmental competencies for important adult responsibilities (e.g. voting) will have been acquired by 18 years of age. In legal terms, young people under the age of 18 in the UK are still provided for under the Children Act of 2004, with parental responsibility taking prominence. However, concepts of competence have changed in recent years to allow young people under the age of 18 years to be able to give consent for their own treatment (see Chapter 35, Ethics) and neuroscience research suggests that adolescent brain development continues well into the third decade. Cultural aspects of a young person’s life are also important in defining a transition from childhood to adulthood. Commencement of adult social roles, such as employment and childbirth, can occur during adolescence. In high-income countries, it is interesting to reflect on the widening gap which exists between childhood and key early adult life events, which have traditionally represented autonomy and independence (such as marriage, first child and leaving the family home). This has mostly been driven by Nwanneka N Sargant, Lee Hudson, Janet McDonagh Adolescent medicine C H A P T E R 32
32 628Adolescent medicine reported having been diagnosed with a long-term medical illness or disability. Furthermore, two thirds of those with a long-term condition were taking medication and one third reported that their condition affected their engagement with school. Long-term pain and chronic health conditions were the most common forms of impairment experienced by older adolescents and young adults. Advances in medical care have resulted in increasing numbers of these young people with chronic illnesses (such as cystic fibrosis, congenital heart disease, inherited metabolic disease, cancer and cerebral palsy) surviving into adulthood, whereas previously they died in childhood. These survival rates have major implications for the development of transitional care provision as young people move from child- to adult-centered health services. A number of long-term conditions are characterized by a peak age of onset in adolescence and young adulthood. These include type 1 diabetes, inflammatory bowel disease, juvenile systemic lupus erythematosus, eating disorders and other mental health disorders. The number of hospital admissions in England among 10–19 year olds for diabetes, epilepsy and asthma has been increasing over the last decade. These increased admission rates raise questions about the standards of care for young people with long-term conditions, particularly around the transfer from paediatric to adult care. Determinants of adolescent health Health is affected by a wide range of social, economic and environmental factors irrespective of the age of the individual. In the UK in 2010–2011, more than a fifth (22%) of young people aged 11–15 years were living in families with the lowest levels of income and at increased risk of ill-health. Adolescence is a key period for establishing both health promoting as well as health risk behaviours, which in turn are influenced by family, peers, local community and education. Since such behaviours track into adulthood, social determinants of adolescent health are crucial to the health and economic development of the society they live in. The strongest determinants of the health of adolescents worldwide are national wealth, income inequality and access to education, closely followed by family, schools and peers. Improving adolescent health will therefore need to consider these issues in addition to improvements in access to education and employment for young people and the reduction of risk of road traffic accidents. In the UK, although participation in further and higher education has increased in socio-economic changes, and in the past 30 years, a significant popular cultural movement has also developed specific to adolescence, with commercial recognition of the influence the adolescent age group has. The rise of this cultural movement has been associated with both positive and negative effects on adolescents. Epidemiology There have never been as many young people in the world as there are now, with a quarter of the global population represented by 10–24-year-olds. In the UK, young people represent 12.5% of the population, a similar proportion to the over 70-year-olds and the 0–9-year-olds. A fifth of adolescents in the UK are from ethnic minorities. Lifelong health behaviours develop during adolescence and therefore it is important to promote healthy lifestyles during this life stage in order to influence long-term health outcomes. Health promotion is discussed in detail later in this chapter. A significant proportion of the 11–18 year age group are overweight or obese (31% of boys and 37% of girls), whilst much smaller proportions of young people meet recommended levels of physical activity, with girls being worse than boys. It is recognized that half of all lifetime cases of psychiatric disorders manifest by age 14 and three quarters by age 24. Studies have shown that approximately 13% of boys and 10% of girls aged 11–15 years have mental health problems, with conduct disorders being most common in boys and emotional difficulties in girls. Mental health is covered in Chapter 24, Child and adolescent mental health, and substance use and sexual activity will be discussed later in this chapter. Long-term conditions or disabilities affect a significant minority of adolescents. One study in England found that one in seven young people aged 11–15 Box 32.1 Definitions pertinent to adolescent medicine WHO definitions: Adolescent: 10–19 years Young people: 10–24 years Youth: 15–24 years Other: Teenage: 13–19 years Young adult: 16–25 years Adolescent developmental stages: 10–13 years: Early adolescence 14–16 years: Mid adolescence 17–19 years: Late adolescence 19+ years: Emerging adulthood