Childhood Headache

Symposium: neurology

Evaluation of headaches in children

by age 15.2 Other studies have reported similar incidences and trends.3 The prevalence of headache increases with age and reaches an adult population prevalence in the early teens. Migraine affects 1–3% of children by age 7 years and 4–11% by age 15 years.4 Abu-Afereh and Russell estimated the prevalence of tension-type headaches in school children to be 0.9%.5 Secondary headaches are rare, and brain tumour as a cause of headache even rarer. For every child with a brain tumour there are around 5000 children with recurrent headaches, including 2000 children with migraine.1 Headaches have a significant impact on the lives of children and adolescents, resulting in school absence,5 decreased extracurricular activities and poor academic achievement. A good history will provide a diagnosis in the vast majority of children. This together with a careful examination will ensure that serious causes are unlikely to be missed. This process should also be therapeutic and reassuring to the parents and child.

Sourabh Mukhopadhyay Catharine P White

Abstract This review provides a practical guide to the common causes of headache and their assessment in children. Contrary to popular belief, headaches are very common in children. The primary headache disorders, which include migraine and tension-type headache, account for the majority of headaches, while secondary headache, i.e. those with underlying pathology, are much less common. A thorough history and examination is the key to determining the cause and should be the most important means of reassuring the child and family that there is no serious cause for the headaches. To manage childhood headache you need to be able to distinguish the painful from the harmful, and therefore must recognize the common headache patterns and the signs and symptoms that may indicate serious intracranial disease. Most non-acute headaches do not need further investigation. Neuroimaging is rarely necessary. Recurrent headaches, of whatever cause, are a cause of considerable morbidity, especially in terms of school absence.

Classifying paediatric headaches In 1988 The International Headache Society6 published a classification scheme for headaches, including complex diagnostic ­criteria. In essence, it divided headache into two categories – ­primary and secondary. Primary headache disorders, i.e. those that have no other underlying cause, include migraine, tensiontype headache and cluster headache. Secondary headaches are associated with underlying central nervous system (CNS) or other pathology. More recently, it was recognized that this classification needed fine tuning, especially in relation to the classification of headaches in children and adolescents, and the revised classification was published in 2004.7 Although standard teaching is to consider migraine and tension headache as completely different entities, it is much more likely that they lie on a continuum.8 This theory fits better with clinical practice. Clinically it can be more helpful initially to divide headache into one of four broad types depending on the temporal pattern9: • isolated acute; • acute recurrent (episodic); • chronic progressive; • chronic non-progressive.  Acute headache is defined as a recent onset headache with no prior history of similar episodes. In children, this pattern is most commonly due to febrile illness related to upper respiratory tract infection,10 but severe acute headache may also be the presenting symptom of a variety of serious intracranial pathologies such as meningitis, raised intracranial pressure or haemorrhage (Table 1). Attacks of head pain separated by symptom-free intervals are classified as acute recurrent headache. Primary headache syndromes, such as migraine or tension-type headache, usually cause this pattern. Infrequently, recurrent headaches are attributable to epilepsy or cluster headache. In chronic progressive headache the frequency and severity of the headaches gradually increases with time. This is the most ominous of the temporal patterns and is commonly correlated with increasing intracranial pressure. Causes include idiopathic intracranial hypertension, tumour, hydrocephalus and subdural collections.

Keywords acute headache; brain imaging; differential diagnosis; ­migraine; tension-type headache

Introduction Headaches are common in children and the prevalence increases with increasing age. In our practice, almost half of referrals from primary care are because of headache. Unfortunately, most parents think that headache is an uncommon symptom in children, hence their understandable concern. As well as hoping to relieve the pain, parents are often seeking reassurance that their child’s headache is not a sign of serious intracranial disease, such as a brain tumour. If this is understood, then we do not need to explain every headache, but we must be able to reassure the child and family that it is not a sign of serious illness. Migraine and tension-type headache are by far the commonest causes of headache.1 Other rarer causes include hemicrania continua, cluster headaches, idiopathic intracranial hypertension and, of course, the headache associated with raised intracranial pressure secondary to a tumour. Studies of Swedish school children have indicated that 39% of children experience headache by 7 years of age and 70%

Sourabh Mukhopadhyay MB BS MRCPCH is a Specialist Registrar in Paediatric Neurology at Morriston Hospital, Swansea, Wales, UK. Catharine P White MB BS FRCP FRCPCH is a Consultant Paediatric Neurologist at Morriston Hospital, Swansea, Wales, UK.

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the headache is important but unfortunately children under 10 years are not good at describing pain, its frequency, severity or distribution. This does not mean that they should not be asked or listened to. Rothner has created a checklist to aid clinicians in eliciting the important features of any headache11 (Table 2). Whilst more applicable to the outpatient setting, it is still a useful aide memoir in the acute situation. In addition, questions need to be specifically asked about other symptoms that suggest raised intracranial pressure or progressive neurological disease, such as unsteadiness, seizures or visual disturbances. Subtle behavioural disturbances or school difficulties can be important early warning symptoms of a structural aetiology, but may also occur when the pain becomes chronic. A past history of head injury or other neurological problems may be relevant. School absence can be a useful proxy measure for the severity of the problem. A family member with headaches may give a clue to the cause but may also be acting as a role model for the headache behaviour. Symptoms that suggest a secondary cause for the headaches are given in Table 3.

Important causes of acute headache • Migraine • Tension headache • Infection ○ Local • Eyes • Ears • Teeth • Sinuses • Skin • Lymph nodes ○  Systemic • Viraemia • Bacteraemia • Meningitis • Encephalitis • Septicaemia • Arterial hypertension • Inflammatory disease ○ Local • Cervical • Musculoskeletal ○  Systemic • Kawasaki disease • Lupus • Other collagen vascular disease • Intracranial ○  Hydrocephalus ○ Intracranial haemorrhage ○  Brain tumour ○  Vascular anomaly ○ Idiopathic intracranial hypertension ○ Post traumatic

Examination The focus of the examination will be determined by the history and clinical context. It is helpful to divide the child presenting with an acute severe headache as an emergency from the child with other temporal patterns of headache as the causes are somewhat different (Tables 1 and 4). Lewis and Qureshi10 found that children presenting to the emergency room with an acute headache most commonly had a febrile illness related to an upper respiratory tract infection. A serious underlying neurological diagnosis was uncommon, and all these patients had clear objective neurological signs. Signs of an infective aetiology, both intra- and

Things to ask about headache11

Table 1

Do you have more than one type of headache? How did the headache begin? Was there associated trauma or infection? How long has the headache been present? Are the symptoms getting better, worse or staying the same? How often do the symptoms occur? How long do they last? Do the headaches occur at any particular time or circumstance? Is the headache preceded by a warning? Where does it hurt? What sort of pain is it? Is it pounding or sharp? Do you have any associated symptoms during the headache? Is there any nausea or vomiting? Do you stop what you are doing during the headache? Are there activities that make the headache worse? Does anything make the headache better? Do you have any other medical problems? Are you taking any medication? Does any one in your family have headaches? What do you think is causing your headache?

Chronic non-progressive headaches differ from acute recurrent headaches by their greater frequency and persistence. They may last for years with no associated neurological symptoms or change in headache severity. A common headache in this category is chronic tension-type headache. An important newly recognized entity that also occurs with this temporal pattern is chronic daily headache.

Clinical assessment of headache in children The cornerstone of headache management remains good history taking and careful physical and neurological examination. This invariably allows a diagnosis to be made, identifies those children who have a secondary cause for their headache and recognizes the few who require further investigation. History The history is the key to diagnosing the cause of the headache and to identifying those children with symptomatic (secondary) headache. Asking both the child and their parents about

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Table 2



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Symposium: neurology

­ ressure. Specific features of the neurological examination that p may indicate a secondary cause are given in Table 5.

Symptoms suggestive of a secondary cause Headache history • Short history ○  ‘First or worst’ headache ○ Recurrent severe headache(s) for a few weeks • Accelerated course ○ Increasing frequency ○  Worsening usual headache • Headache timing and posture ○ Mainly from sleep ○ In the morning before getting up ○ Mainly or worse when lying down, relieved when upright (suggests raised pressure) ○  Worse with bending, coughing, etc ○ Mainly upright, relieved when lying down (suggests low pressure headache)

Investigation Careful history taking and examination should allow identification of the few children who require further investigation. It is again helpful to divide the investigation of the child with an acute severe headache from the child with other temporal patterns of headache as the investigations that need to be considered are different. Acute severe headache In acute severe headache, routine laboratory investigations may be helpful given that intercurrent infection is the commonest cause. Lumbar puncture with measurement of the opening pressure may be needed if subarachnoid haemorrhage, meningitis or idiopathic intracranial hypertension are diagnostic possibilities. Skull X-ray and EEG are of extremely limited value. An urgent initial computerized tomography (CT) scan may be required if acute hydrocephalus, haemorrhage or a structural lesion are suspected. A CT brain scan with contrast will demonstrate nearly all structural lesions; one done without contrast is somewhat more limited in its sensitivity, although it can define hydrocephalus and haemorrhage easily. Magnetic resonance imaging (MRI) is less readily available; less good at demonstrating acute blood and makes monitoring the ill patient more difficult so it is not the initial method of choice in this situation.13 Table 6 lists the features in the history and examination that indicate imaging should be strongly considered.

Associated symptoms ○  Vomiting from sleep or before getting up ○  Confusion, impaired consciousness ○  Altered personality ○  Focal weakness ○  Diplopia ○  Fever, rigors ○  Seizures Table 3

extra-cranial, must therefore be specifically sought; as well as signs of acutely raised pressure and intracranial haemorrhage. In the outpatient setting most children will have acute recurrent or chronic non- progressive headaches, but it is the rare child with chronic progressive headaches that we need to identify. Table 4 lists the major causes of headache in the clinic ­population.12 Given this list it is not surprising that the clinical examination in this situation is invariably normal. Important aspects of the general physical examination are height, weight and blood

Other temporal patterns of headache In the outpatient setting the cause for the child’s headache is usually clear from the history and examination. Neuroimaging is rarely necessary and of little value, unless the history or examination suggests a structural aetiology. If the history is typical for migraine and the neurological examination is normal, no imaging is required. Raised intracranial pressure due to a tumour is the major concern for the family and the referring clinician; however, the symptoms and signs should rarely

Major causes of headache in the clinic population12 Diagnosis

Percentage

Migraine without aura Migraine with aura Complicated migraine Episodic tension-type headache Chronic tension–type headache Mixed common migraine and episodic tension headache Mixed common migraine and chronic tension headache Non-specific headache Other specific diagnoses or combinations

24.3    6.0    2.4 15.0 23.9    4.2

Signs suggestive of secondary headache Signs of raised intracranial pressure • Large or accelerating head circumference • Cracked pot sign • Papilloedema • IV nerve palsy Other signs of CNS disease • Other cranial nerve palsies • Brainstem signs • Other focal neurological signs, e.g. hemiplegia • Cerebellar signs, e.g. ataxia, nystagmus

   6.2 12.3    6.0

Signs of other systemic disease

Table 4

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Table 5



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­children or their parents are any different. Given the potential risks of neuroimaging, which include incidental findings that increase the concern of the patient or parents, false reassurance from an inadequate study, the risks of an allergic reaction to iodine contrast media with CT scanning, and the risk of sedation in young children or claustrophobic patients having MRI scans; we should continue to try to avoid imaging for reassurance.

Indications for neuroimaging in patients with acute headache Signs and symptoms of elevated intracranial pressure Meningeal signs + focal neurological findings or altered mental status Progressive or new neurological signs Significant head trauma Severe (‘worst headache of life’) headaches of increasing frequency and duration Presence of VP shunt

Specific headache syndromes As the history is so important in making the diagnosis, this section details the features and diagnostic criteria for the two common causes of headache – migraine and tension-type headache. It is important to recognize that a mixed pattern of migraine and tension-type headache is common.

Table 6

Migraine headaches Paediatric migraine is now distinctly recognized among the primary headache disorders. The diagnostic criteria for migraine are broader in children than they are in adults and allow for a wider range of duration and localization of the pain. In practice, paediatric migraines are often bilateral and clear localization of the pain can be difficult to obtain from children. In general, attacks in children last for a shorter time than in adults.19 They are ­ frequently preceded by a behavioural prodrome with mood changes or withdrawal from activity. The classical history obtained in adults of unilateral throbbing/pounding pain lasting greater than 4 h becomes commoner with age. Migraine with aura is seen in 14–30% of children with migraine. Typical auras are spots, colours, image distortions or visual scotoma. Migraine commonly ‘runs in families’ with approximately 70% of children having an affected first-degree relative.20 Earlier attempts to define migraine used this strong familial occurrence as one of the diagnostic features of migraine. The new diagnostic criteria set by the International Headache Society (IHS) are described in Table 7. Complicated migraines are headaches that are accompanied or manifested by transient neurological symptoms. These ­symptoms may occur immediately before, during or after the headache. In some situations, the headache may be mild or non-existent. Hemiplegic migraine, ophthalmoplegic migraine and basilar artery migraine are typical examples of complicated migraine. Hemiplegic migraine, while unusual, is seen more commonly in children than in adults. It is characterized by abrupt onset of hemiparesis, which usually is followed by a headache. Hemianaesthesia may also precede the headache. Ophthalmoplegic migraine may occur at any age, and usually is associated with orbital or periorbital pain, as well as third, fourth or sixth cranial nerve involvement. The headache resolves in hours, but the ophthalmoplegia may last for days. Basilar artery migraines are characterized by dizziness, weakness, ataxia and severe occipital headache (with vomiting).

be mistaken for other benign causes of headache and brain tumours account for less than 0.1% of the lifetime prevalence of ­headaches.14 All patients who present with symptoms and/or signs suggestive of a secondary intracranial cause (Tables 3 and 5) for their headaches should undergo high-quality imaging. MRI is generally more costly, takes longer and may require sedation, but its superior imaging capabilities offer detailed structural definition not available from CT scanning even with contrast. Neuroimaging should be considered in those with a significant change in headache symptomatology or who are younger than 3 years of age. The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society reviewed the literature on the evaluation of the child with recurrent headaches and concluded that routine laboratory investigations, lumbar puncture and EEG are not necessary.15 They also concluded that neuroimaging is not indicated in children with a normal neurological examination. In the studies they reviewed, all the children with CNS lesions who required surgical treatment had definite abnormalities on examination. They recommended neuroimaging be considered in children with: • recent onset of headache (less than 1 month’s duration); • features in the history suggestive of neurological dysfunction; • abnormal neurological findings on examination; • occurrence of seizures.  Variables that predicted a space-occupying lesion included the above plus gait abnormalities and the absence of family history of migraine. Repeated studies looking at the yield of neuroimaging in children with uncomplicated migraine or tension-type headaches and a normal neurological examination have found small but significant numbers of abnormalities, none of which has influenced the diagnosis, management or outcome for the patient.16,17 It is sometimes suggested that scanning is reassuring to the patient and their family but a randomized control trial of imaging in adults with chronic daily headache showed that MRI scanning only temporarily reduced their anxiety about the cause of their headaches. At 1 year there was no difference between the scanned and the non-imaged groups and having a scan did not improve most other measures of health anxiety, illness perceptions or quality of life.18 There is no reason to suspect that

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Tension-type headache Tension-type headaches are more common in adults than children. The revised IHS classification distinguishes three subtypes depending on frequency – infrequent episodic, frequent episodic and chronic. Tension-type headache is usually bilateral and described as pressing or band-like. These headaches 

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Symposium: neurology

for the latter the pain may be continuous and mild nausea may occur. The picture may be complicated and perpetuated by inappropriate and ­excessive analgesia use. Chronic daily headache (CDH) was first described in adults who reported daily or nearly daily headaches. It was soon recognized that, although patients were similar in the number of headaches experienced, the characteristics of their headaches fell on a continuum between migraine and tension-type headache. Recent work has demonstrated a similar spectrum in children. The most common CDH pattern is superimposition of migraines on a background pattern of frequent tension-type headaches, but other categories are recognized based on the specific clinical features and the pattern of evolution.21 ◆

International Headache Society diagnostic features of migraine Migraine without aura A. At least five attacks fulfilling B–D B. Duration between 1 and 48 h C. At least two of the following: • Bilateral or unilateral • Pulsating • Moderate to severe in intensity • Aggravation by routine physical activity D. During the headache at least one of the following: • Nausea or vomiting • Photophobia or phonophobia E. Not attributable to another disorder

References 1 Abu-Arafeh I, Macleod S. Serious neurological disorders in children with chronic headache. Arch Dis Child 2005; 90: 937–940. 2 Bille BS. Migraine in school children. A study of the incidence and short term prognosis, and a clinical, psychological and electroencephalographic comparison between children with migraine and matched controls. Acta Paediatr 1962; 51(suppl 136): 1–151. 3 Sillanpaa M, Abu-Arafeh I. Epidemiology of recurrent headache in children. In: Abu-Arafeh I, ed. Childhood headache. London: MacKeith Press, 2002, p. 19–34. 4 Lipton RB. Diagnosis and epidemiology of pediatric migraine. Curr Opin Neurol 1997; 10: 231–236. 5 Abu-Arefeh I, Russel G. Prevalence of headache and migraine in school children. BMJ 1994; 309: 765–769. 6 Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia 1998; 8(suppl 7): 1–96. 7 Headache Classification Committee of the International Headache Society. The international classification of headache disorders. Cephalalgia 2004; 24(suppl 1): 1–160. 8 Viswanathan V, Bridges SJ, Whitehouse W, et al. Childhood headaches; discrete entities or continuum? Dev Med Child Neurol 1998; 40: 544–550. 9 Rothner AD. Headaches in children. A review. Headache 1978; 18: 169–175. 10 Lewis DW, Qureshi F. Acute headache in children and adolescents presenting to the emergency department. Headache 2000; 40: 200–203. 11 Rothner AD. Headaches. In: Swaiman KF, Ashwal S, eds. Paediatric neurology: Principles and practice. St Louis: Mosby, 1999, p. 747–758. 12 Abu-Arafeh I, Callaghan M. Headache clinics for children. In: Abu-Arafeh I, ed. Childhood headache. London: MacKeith Press, 2002, p. 175–184. 13 Stoodley N. Neuroimaging in children. Curr Paediatr 2003; 13: 479–485. 14 Rasmussen BK. Epidemiology of headache. Cephalalgia 1995; 15: 45–68. 15 Lewis DW, Ashwal S, Dahl G, et al. Practice parameter: Evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002; 59: 490–498.

Migraine with aura A. In addition to above criteria, at least two attacks fulfilling B B. At least three of the following: • One or more fully reversible aura symptoms indicating focal cortical or brainstem dysfunction • Aura developing gradually over minutes, or two or more symptoms occurring in succession • Aura lasts no more than 1 h • Pain follows aura after <1 h Table 7

can last for days and are not aggravated by physical activity. Nausea, vomiting, photophobia and phonophobia are not typical accompaniments. The IHS criteria for the diagnosis of infrequent tension-type headache are described in Table 8. Frequent episodic tension-type headache is defined as occurring on greater than 1 but less than 15 days a month for at least 3 months, while chronic tension-type headache occurs for greater than 15 days per month for at least 3 months. Episodic and chronic tension-type ­headaches have same physical ­characteristics, but

International Headache Society criteria for the diagnosis of infrequent tension-type headache A. At least 10 episodes occurring on <1 day per month on average (<12 days per year) and fulfilling criteria B–D B. Headache lasting from 30 min to 7 days C. Headache has at least two of the following characteristics 1. bilateral location 2. pressing/tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. no nausea or vomiting (anorexia may occur) 2. no more than one of photophobia or phonophobia E. Not attributed to another disorder Table 8

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Symposium: neurology

16 Worber-Bingol C, Wober C, Prayer D, et al. Magnetic resonance imaging for recurrent headache in childhood and adolescence. Headache 1996; 36: 83–90. 17 Lewis DW, Dorbad D. The utility of neuroimaging in the evaluation of children with migraine or chronic daily headache who have normal neurologic examinations. Headache 2000; 40: 629–632. 18 Howard L, Wessely S, Leese M, et al. Are investigations anxiolytic or anxiogenic? A randomised controlled trial of neuroimaging to provide reassurance in chronic daily headache. J Neurol Neurosurg Psychiatry 2005; 76: 1558–1564. 19 Maytal J, Young M, Shecter A, et al. Pediatric migraine and the International Headache Society criteria. Neurology 1997; 48: 602–607. 20 Condgen PJ, Forsythe WI. Migraine in childhood: a study of 300 children. Dev Med Child Neurol 1979; 21: 209–216. 21 Gladstein J, Holden EW. Chronic daily headache in children and adolescents: a 2 year prospective study. Headache 1996; 36: 349–351.

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Practice points • Headache is common in children • The history is the key to diagnosis • Many parents are simply seeking reassurance that their child does not have a brain tumour • Neuroimaging is rarely necessary unless the history or examination suggests a structural aetiology • Headache due to a space-occupying lesion is very rarely an isolated symptom and there are invariably accompanying neurological signs • Adult definitions of migraine do not always apply to children and there is likely to be a continuum between migraine and tension-type headache.



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Symposium: Neurology

Management and outcome of viral encephalitis in children

of patients with suspected VE has changed dramatically in recent years, with improved viral diagnostics and imaging studies, better antiviral and immunomodulatory therapies, and enhanced neurointensive care and rehabilitation. This review aims to provide a rational approach to the investigation and treatment of children and infants older than 28 days with suspected and proven VE.

Rachel Kneen

What do we mean by encephalitis?

Tom Solomon

Encephalitis means inflammation of the brain parenchyma. It can be caused directly by a range of viruses (Table 1) and other microorganisms (Table 2). Encephalitis can also occur as an immune-mediated phenomenon, e.g. in acute disseminated encephalomyelitis (ADEM), which often follows infections or vaccinations (Table 2). Encephalitis is strictly a pathological diagnosis that should only be made if there is tissue confirmation (autopsy or brain biopsy). This is clearly not very practical. Therefore, most patients are diagnosed with encephalitis if they have the appropriate clinical presentation and surrogate markers of brain inflammation, such as inflammatory cells in the cerebrospinal fluid (CSF) or inflammation shown on imaging, especially if an appropriate organism is detected. Encephalitis is different from encephalopathy, which is the clinical syndrome of reduced consciousness associated with other infectious diseases, metabolic disorders and drugs. Metabolic and toxic causes of encephalopathy can usually be distinguished from VE by the lack of an acute febrile illness, more gradual onset, lack of a CSF pleocytosis and absence of focal changes on magnetic resonance imaging (MRI).4 The organisms that cause encephalitis often also cause an associated meningeal reaction (meningitis). In this clinical situation, the term meningoencephalitis is sometimes used. However, others use this term to cover the full spectrum of encephalitis and meningitis; this should be discouraged because the clinical features, investigations and treatment differ. Spinal cord inflammation (myelitis) or nerve root involvement (radiculitis) may also occur in viral central nervous system (CNS) infections.

Abstract Although viral encephalitis (VE) is relatively uncommon in children in the UK, early recognition and appropriate investigation and management are essential because of the devastating nature of the condition. An estimated 1200 paediatric cases from all causes are admitted each year. The cause of VE is diagnosed in approximately 30% of cases. The commonest cause in the UK is herpes simplex virus type 1 but ­globally the most important cause is Japanese encephalitis virus. Diagnostic methods have improved recently and the yield can be increased with a rational approach to investigations and by taking specialist advice. Morbidity and mortality are high but can be significantly reduced in herpes simplex ­virus encephalitis by treating for at least 14 days with intravenous aciclovir. Sequelae are common and include motor, sensory and cognitive impairments, epilepsy, behaviour problems and psychiatric disorders. ­ Children should have access to a neurorehabilitation team, which includes a neuropsychologist, to achieve the best recovery possible. Long term follow-up and an organized transition into adult services is required. Q2

Keywords aciclovir; central nervous system infection; herpes simplex virus; meningoencephalitis; viral encephalitis

Introduction Viral encephalitis (VE) is uncommon in the UK. A typical district general hospital could expect to see approximately five paediatric cases per year.1 However, it is very common for a child to present with symptoms for which the differential diagnosis includes VE. These children are started on intravenous aciclovir and broadspectrum antibiotics and treated for a variable length of time before either an alternative diagnosis is made or the diagnosis of VE is confirmed. In these children, the approach to making a diagnosis and the length and route of treatment with aciclovir is often variable. Guidelines for the management of adult patients with suspected encephalitis have been drawn up2,3 and are in the process of being modified/ratified for national usage. ­Similar guidelines are in development for children with suspected VE. The management

What causes the clinical picture in viral encephalitis? Depending on the virus, the pathogenesis can consist of a mixture of direct viral cytopathology and a para- or post-infectious inflammatory or immune-mediated response. For most viruses, the brain parenchyma and neuronal cells are primarily infected, but for some, the blood vessels can be attacked, giving a strong vasculitic component. Demyelination following infection can also contribute. Herpes simplex virus (HSV), for example, primarily targets the brain parenchyma on the temporal lobes, sometimes with frontal or parietal involvement. Mumps virus can cause an acute VE or an immune-mediated delayed encephalitis. Measles virus causes a post-infectious encephalitis, which can sometimes have a severe haemorrhagic component (acute haemorrhagic leukoencephalitis). For influenza A virus a diffuse cerebral oedema is a major component in the pathogenesis, while for varicella zoster virus (VZV), vasculitis is a major pathogenic process. Viruses must cross the blood−brain barrier to cause encephalitis. Primary infection with HSV type 1 (HSV-1) occurs in the oral mucosa. Following primary infection the virus travels

Rachel Kneen MRCPCH is a Consultant Paediatric Neurologist at the Department of Neurology, Littlewoods Neuroscience Foundation, Royal Liverpool Children’s NHS Trust, Alder Hey, Liverpool, L12 2AP, UK. Tom Solomon FRCP is Chair of Neurology and heads the Brain Infections Group at the University of Liverpool, Walton Centre for Neurology and Neurosurgery, Liverpool, L9 7LJ, UK.

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Symposium: Neurology

Causes of acute viral encephalitis in children (modified from ref.28)

Diseases mimicking viral encephalitis in children (modified from ref.28)

Sporadic causes of viral encephalitis (not geographically restricted) listed by group Herpes viruses • Herpes simplex virus type 1 and 2 • Varicella zoster virus • Epstein-Barr virus • Cytomegalovirus • Human herpes virus types 6 and 7 Enteroviruses • Coxsackieviruses • Echoviruses • Enteroviruses 70 and 71 • Parechovirus • Poliovirus Paramyxoviruses • Measles virus • Mumps virus Others (rarer causes) • Influenza viruses • Adenovirus • Parvovirus • Lymphocytic choreomeningitis virus • Rubella virus

CNS infections Bacteria Bacterial meninigitis Tuberculous meningitis Brain abscess Typhoid fever Parameningeal infection Lyme disease Leptospirosis Mycoplasma pneumonia Listeria monocytogenes Brucellosis Subacute bacterial endocarditis (emboli) Fungi Cryptococcus Coccidiomycosis Histoplasmosis Candidiasis Parasites Cerebral malaria Toxoplasmosis Cysticercosis Rickettsiae Typhus Q fever Erlichiosis Cat-scratch fever

Q3

 Geographically restricted causes of encephalitis – mostly arthropod-borne* The Americas • West Nile • La Crosse • St Louis • Dengue • Rabies Europe/Middle East • Tick-borne encephalitis • West Nile • Rabies Africa • West Nile • Rift Valley fever virus • Crimean-Congo haemorrhagic fever • Dengue • Rabies Asia • Japanese encephalitis • West Nile • Dengue • Murray Valley encephalitis • Rabies • Nipah Australasia • Murray valley encephalitis • Japanese encephalitis

 Non-infectious diseases Vasculitic Systemic lupus erythematosis Acute haemorrhagic leukoencephalitis Acute necrotizing encephalopathy Polyarteritis nodosa ANCA associated vasculitis Neoplastic Primary brain tumour Brain metastases Paraneoplastic limbic encephalitis+ Metabolic Diabetic ketoacidosis and coma Hepatic encephalopathy Hypertensive encephalopathy Haemolytic uraemic syndrome Hypoglycaemia Reye syndrome Mitochondrial encephalopathy Toxic encephalopathy (drugs, alcohol) Other Drug reactions Subarachnoid and subdural haemorrhage Venous sinus thrombosis and infarction Ischaemic cerebrovascular accidents Epileptic encephalopathy or nonconvulsive status epilepticus Functional illness Voltage-gated K channel limbic encephalitis+

*Guillain–Barré syndrome and acute disseminated encephalomyelitis may follow viral or bacterial infections or vaccinations. +Very rare in children.

Table 2

c­ entripetally along the trigeminal nerve to give latent infection in the trigeminal ganglion. About 70% of all cases of HSV encephalitis already have antibody present, indicating re-activation of virus is the most common mechanism;5 though it is not clear

*All viruses are arthropod-borne, except for Rabies and Nipah virus.

Table 1

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Para/post-infectious causes Guillain-Barré syndrome* Acute disseminated encephalomyelitis* Systemic viral illnesses with complex febrile convulsions Acute haemorrhagic leukoencephalitis Acute necrotizing encephalopathy



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Symposium: Neurology

whether this is re-­activation of virus in the trigeminal ganglion or virus that has already established latency in the brain itself.6 Why HSV ­sometimes re-activates is not known. In young adults and children, HSV encephalitis occurs during primary infection. Neonates can be infected with HSV-2 during delivery to cause neonatal herpes, a disseminated infection often with CNS involvement. This review does not cover neonatal herpes infection in detail (see Useful websites and further reading). HSV-2 also causes viral meningitis in adults, which may be recurrent. HSV-2 is predominantly sexually acquired and the diagnosis of HSV-2 meningitis in a child should alert the paediatrician to the possibility of sexual abuse.7 The other major route of viral entry into the nervous system is with a viraemia and subsequent spread across the blood–brain barrier; this occurs for enteroviruses such as polio, and arbo­ viruses (viruses transmitted via an insect or tick vector) such as Japanese encephalitis virus (JEV) and West Nile virus (WNV).

altered consciousness. There may be meningism, seizures and focal neurological signs. The subtle presentation is with low grade fever, behavioural changes or speech and language disturbance.10 The subacute presentation is more common in immunocompromised patients.

Important features in the history As well as being crucial in determining who needs investigation for VE, the history can provide useful clues as to the ­aetiology: • recent rash (patient or contacts) – measles, chicken pox (VZV), slapped cheek syndrome (parvovirus), hand, foot and mouth disease [enterovirus (EV)] or roseola (HHV-6). See ­examination findings below; • parotitis, testicular pain or abdominal pain (pancreatitis) – mumps; • dog bite, scratch from bat – rabies; • travel history – South East Asia (JEV); forests in central ­Europe [tick borne encephalitis virus (TBEV)]; • social history – mother from HIV endemic area or intravenous drug abuser.

Epidemiology The epidemiology of VE is changing for several reasons: • Numbers of immunocompromised patients have increased due to human immunodeficiency virus (HIV) infection, transplant surgery and cancer treatments. These patients are at risk of encephalitis caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6). • Arboviruses are spreading to new areas, e.g. WNV across North America and southern Europe, and JEV across Asia. • Large and unexpected outbreaks of VE have occurred in Asia from enterovirus (EV) 71 and Nipah virus.8,9 • Vaccination has reduced encephalitis due to measles and mumps virus.

Important examination findings The priority is to stabilize the patient and treat immediate complications such as seizures. Make an assessment of level of coma using the modified Glasgow coma score (GCS). Do not ignore the parents who tell you their child is confused or has altered behaviour. Other important examination findings are: • rashes – exanthems (many viruses), e.g. hand, foot and mouth disease (EV71), purpuric rash (meningococcal meningitis); • meningism or photophobia – check for neck stiffness and Kernig’s sign; • signs of raised intracranial pressure (RICP) – altered pupillary responses, raised blood pressure, bradycardia, altered respiratory pattern, abnormal posture (decorticate or decerebrate), papilloedema; • focal neurological signs – hemiplegia, cranial neuropathies, abnormal posturing (see above); • tonic eye deviation, nystagmus, subtle clonic movements of face or fingers – subtle motor status epilepticus; • lower cranial neuropathies – rhomboencephalitis/basal meningoencephalitis (enteroviruses or listeria, tuberculosis).

Incidence The incidence of VE depends on the particular viruses that are prevalent. Currently, accurate figures for the UK are unknown. This is being addressed in a prospective study (funded by the Health Protection Agency), which is currently enrolling patients from many centres in England (www.hpa.org.uk/infections/ topics%5Faz/encephalitis/study.htm). For children, the best extrapolation we can use at present are data from Finland. In a 2-year prospective study (1993/4), Koskiniemi et al found that the overall incidence was 10.5 in 100 000 child-years, with the highest figure in children younger than 1 year of age (18.4 in 100 000 child-years). The most commonly identified agents, based on virological and serological studies, were VZV, respiratory viruses, enteroviruses, adenoviruses, EBV, HSV, rotaviruses and HHV-6.1 For adults and children, HSV encephalitis is the most commonly diagnosed VE in developed countries, with an incidence of 1 in 250 000–500 000.5 Most HSV encephalitis is due to HSV-1, but about 10% are due to HSV-2; the latter causes encephalitis in immunocompromised adults and neonates, in whom it causes a disseminated infection.

Initial investigations A cause is found in approximately 30% of children with VE. It is likely this figure could be improved if more detailed virological tests were undertaken (see below). This is another of the aims of the Health Protection Agency study (see Useful websites and further reading). Some features and clues may be present in the baseline investigations: • full blood count – atypical lymphocytes in EBV; • hyponatraemia – syndrome of inappropriate antidiuretic hormone (SIADH) common in many encephalitides; • elevated amylase – mumps; • elevated liver enzymes – EBV, cytomegalovirus (CMV).

Presentation The classical presentation is a brief flu-like prodrome immediately followed by severe headaches, nausea, vomiting and

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HSV ­encephalitis, PCR remains positive in about 80% of patients even 1 week after starting antiviral therapy.5 CSF findings in VE are shown in Table 4. The CSF opening pressure is often mildly raised and there is usually a mild to moderate CSF pleocytosis of 5 to 1000 cells/mm3, with predominant lymphocytes. CSF white cell count may be normal in the first few days of the infection or neutrophils may predominate. The CSF red cell count is usually normal or mildly elevated, but it may be ­markedly raised in HSV encephalitis, which can be haemorrhagic, or in acute necrotizing haemorrhagic leukoencephalitis. The ­glucose ratio is usually normal in viral CNS infections, though it may be mildly reduced, especially with mumps infection. The CSF protein is often mildly elevated (between 0.5 and 1.0 g/litre).

CSF findings The use of lumbar puncture (LP) in suspected CNS infection has been controversial and has declined recently.11 However, the LP is an essential investigation in suspected CNS infection because: • Initial findings are available within hours and reveal whether or not there is an infection. On rare occasions, the initial cell count may be normal early in the disease process or if the child is immunocompromised. In this circumstance, if CNS infection is still strongly suspected, the LP may need to be repeated. • Initial findings are often able to distinguish between bacterial and viral infection (see Table 4). • Culture, antibody studies and polymerase chain reaction (PCR) of CSF confirm what the organism is. This allows therapies to be altered and appropriate treatment regimens to be given. • Positive results allow appropriate disease notification. • Results may alter follow-up arrangements for the child, e.g. hearing tests, long term developmental follow-up, etc. • Parents find it easier to understand their child’s illness if a diagnosis has been confirmed, especially if the child dies or has long term sequelae. Therefore, an LP should be undertaken unless specific contra­ indications are present (Table 3). An LP is not contraindicated in children who are only mildly confused or lethargic. If focal neuro­logical signs or coma are present, an LP should still be possible after performing a CT scan, if the latter shows no evidence of brain shift. A CT should also be performed in children who may be immunocompromised as they may not mount an inflammatory response to an abscess. Very often, a child is admitted and treatment for bacterial meningitis and encephalitis is started before an LP is performed. In these children, it is still essential to perform an LP when safe to do so because this informs the diagnosis and guides subsequent management.12 Giving blind antibacte­rial and antiviral treatment to all patients with ­suspected CNS infection, and then not investigating with LP because it ‘makes no ­difference to the management’ is unacceptable practice and should be discouraged. This approach risks missing other dia­gnoses that may require alternative treatments.13 In

Specific investigations to consider The list of possible investigations for VE is considerable. Our practice is to perform the initial CSF PCR for α-herpes viruses (HSV-1 and -2, and VZV) (see below) immediately the samples are received, because of their importance for early management. Further investigations are guided by the clinical picture, especially the patient’s immune status, and initial CSF findings. The opinion of a clinical virologist should be sought before undertaking these investigations. A staged approach should be undertaken (Table 5). PCR of CSF Many important viruses and other microorganisms can now be detected using PCR.14 For HSV, PCR has high sensitivity and specificity (both greater than 95%); however, it may be negative in the first few days of the illness or after about 10 days.15 Initial investigations for patients with VE should therefore include PCR for HSV, and probably VZV, because these are potentially ­treatable with aciclovir. If it is the summer or autumn, PCR for EV (­coxsackievirus types A and B, echoviruses and the new enterovirus types such as EV71) should also be performed; measles and mumps should be looked for if there is a clinical indication, but they can occasionally cause encephalitis in patients without the typical features. Other viruses to consider include HHV-6 and -7 (especially in young children), adenovirus, influenza virus A and B, and rotaviruses. In immunocompromised patients with EBV and CMV, PCR should also be performed and HHV-6 considered. PCR can also be used to detect Mycoplasma pneumoniae in the CSF. CSF viral culture is now rarely performed, though it has the advantage over PCR of potentially being able to detect any viruses, whereas PCR is specific to the virus being looked for.

Contraindications to lumbar puncture • Signs of RICP – altered papillary responses, absent Doll’s eye reflex, decerebrate or decorticate posturing, abnormal respiratory pattern, papilloedema, hypertension and bradycardia • Recent (within 30 min) or prolonged (>30 min) convulsive seizures • Focal or tonic seizures • Other focal neurological signs – hemi/monoparesis, extensor plantar responses, ocular palsies • GCS < 13 or deteriorating level of consciousness • Strong suspicion of meningococcal infection (typical purpuric rash in an ill child) • State of shock • Local superficial infection • Coagulation disorder

Further investigations The following may be helpful in VE and should be considered in conjunction with a clinical virologist: • Serum IgM for specific viruses, particularly HSV, EV, EBV and CMV. Compare with IgM in CSF (see below). • CSF IgM for specific viruses, particularly HSV, EV, EBV and CMV. The detection of specific IgM in the CSF, higher than levels in the serum, is an indication that antibody is being produced ­locally in the CNS in response to infection. (In general, though, IgM is only elevated for primary infections rather than re-activation.) • PCR and/or culture of throat and rectal swabs for EV and rotavirus.

Table 3

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Typical cerebrospinal fluid findings in central nervous system infections Viral meningoencephalitis

Acute bacterial meningitis

Tuberculous meningitis

Fungal

Normal

Opening pressure

Normal/high

High

High

High-very high

Colour Cells/mm3

‘Gin’ clear Normal-high 0–1000 Lymphocytes Normal Normal-high (0.5–1.0)

Cloudy High-very high 1000–50,000 Neutrophils Low High (>1)

Cloudy/yellow Mild elevation 25–500 Lymphocytes Low-very low (e.g. <30%) High-very high (1.0–5.0)

Clear/cloudy Normal-high 0–1000 Lymphocytes Normal-low Normal-high (0.5–5.0)

Age < 8 years < 13.5 cm3 Age > 8 years < 20 cm3 Clear <5

Differential CSF:plasma glucose ratio Protein (g/L)

Lymphocytes 66%* <0.5 Q4

A bloody tap will falsely elevate the CSF white cell count and protein. To correct for a bloody tap, subtract 1 white cell for every 700 red blood cells/mm3 in the CSF, and 0.1 g/dL of protein for every 1000 red blood cells. *Although a normal CSF:plasma glucose ratio is quoted as 66%, only values < 50% are likely to be significant. Some important exceptions In viral CNS infections, an early LP may give predominantly neutrophils, or there may be no cells in early or late LPs. In patients with acute bacterial meningitis that has been partially pre-treated with antibiotics (or patients < 1 year old), the CSF cell count may not be very high and may be mostly lymphocytes. Tuberculous meningitis may have predominant CSF polymorphs early in the infection. Listeria can give a similar CSF picture to TBM, but the history is shorter. CSF findings in bacterial abscesses range from near normal to purulent, depending on location of the abscess, and whether there is associated meningitis or rupture. A cryptococcal antigen test (CRAG) and Indian ink stain should be performed on the CSF of all patients in whom cryptococcus is possible.

Table 4

• PCR, culture, and antigen detection of nasopharyngeal aspirates for respiratory viruses, e.g. adenoviruses or influenza ­viruses. • PCR, electron microscopy from vesicular fluid – chicken pox (VZV), hand foot and mouth disease (EV71), genital herpes (HSV-2). • Cold agglutinins and IgM for Mycoplasma pneumoniae if ­respiratory infection is present. • Brain biopsy for PCR, culture, antigen detection, histology – consider if this will change management when diagnosis unclear. Decision should be made with a paediatric neurologist and ­neurosurgeon.

(PLEDS) were once thought to be diagnostic of HSV encephalitis, but have since been seen in other conditions ­(Figure 4).

Management The management of VE covers the acute presentation, recovery and rehabilitation stages. Often children are transferred to a ­tertiary centre which has facilities for acute brain injury rehabilitation. Broadly speaking, the management comprises of: 1. Stabilization of the patient – this may require ventilation and transfer to a paediatric intensive care unit. 2. Control of immediate complications, e.g. seizures, RICP. 3. Antiviral or immunomodulatory treatment. 4. General supportive measures, e.g. hydration, safe feeding, treatment of infections such as pneumonia, urinary tract infections. 5. Prevent later complications, e.g. contractures, venous ­thrombosis. 6. Neurorehabilitation, including all therapy modalities (physiotherapy, occupational therapy, speech and language therapy and psychology). 7. Specialist educational assessment and provision. 8. Treatment of later complications, e.g. epilepsy, spasticity. 9. Continued neuropsychology for specific sequelae (see below).

Imaging and EEG studies As described above, in patients with encephalopathy and fever, a computerised tomography (CT) scan (with contrast) is performed before LP if there are clinical signs suggestive of herniation or a space occupying lesion. In HSV encephalitis, CT may be normal initially, or there may be subtle swelling of the fronto-­temporal region with loss of the normal gyral pattern; subsequently there is hypodensity, and there may be high signal change if haemorrhagic transformation occurs (Figure 1). MRI is generally more sensitive, showing high signal intensities in the brain areas affected (Figures 2 and 3), though even MRI can be normal if performed very early.16 Diffusion-weighted MRI may be especially useful at demonstrating early changes.17 Gadolinium should be given during the MRI scan. An EEG usually shows non-specific, diffuse, high amplitude slow waves of encephalopathy, but can be useful in looking for subtle motor seizures. Periodic lateralized epileptiform discharges

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Seizures, raised intracranial pressure and other complications Seizures are common in VE and status epilepticus may occur, which can be refractory.18 Seizures may be obvious (focal or ­generalized tonic–clonic) or subtle, which may manifest as twitching of a digit or around the mouth or eyes. An EEG should 11

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Staged approach to microbiological investigation of suspected viral encephalitis in children CSF PCR 1. All patients • Herpes simplex virus (HSV) type 1 (type 2 usually also performed by lab), varicella zoster virus (VZV) 2. If indicated: • Enterovirus and parechovirus (especially if meningoencephalitis picture, summer/autumn) • Adenovirus (ADV), influenza (Inf ) A and B, rotavirus (winter/spring) • Epstein-Barr virus/cytomegalovirus (CMV) (especially if immunocompromised) • Human herpes virus (HHV) 6 and 7 (young children or immunocompromised) • Measles, mumps (if clinically indicated, contact Public Health Lab for advice) • Mycoplasma pneumoniae (if respiratory infection present) 3. Special circumstance • Rabies, Japanese encephalitis virus, West Nile virus, dengue, tick-borne encephalitis virus (if appropriate exposure history) Antibody testing 1. Viruses: IgM IgG, oligoclonal bands of CSF and serum (acute and convalescent) for antibodies against: • HSV (1 and 2), VZV, CMV, HHV6, HHV7, enteroviruses, respiratory synctial virus, ADV, Inf A and B; 2. If associated with atypical pneumonia, test serum for: • Mycoplasma pneumoniae serology and cold agglutinins • Chlamydia serology

Figure 1 CT scan showing oedema in left temporal lobe with effacement of left lateral ventricle and overlying sulci in HSV type 1 encephalitis.

and positioning; and the risk of joint contractures reduced with passive and active limb movements, and orthoses. To reduce the risk of pneumonia, the risk of aspiration should be assessed. Enteral feeds should be given via a nasogastric tube until swallow safety is assessed.

Ancillary investigations 1. Throat swab (TS), nasopharyngeal aspirate (NPA), rectal swab (RS): • PCR/culture of TS, RS for enteroviruses • PCR of TS for Mycoplasma pneumoniae, chlamydia • PCR/antigen detection of NPA for respiratory viruses, ADV, Inf 2. Vesicle electron microscopy and culture: • Patients with herpetic lesions (for HSV, VZV) • Children with hand, foot and mouth disease (for enteroviruses) 3. Brain biopsy

Aciclovir In most immunocompetent patients, aciclovir should be given as soon as there is a strong suspicion of VE. This suspicion will be based on the clinical presentation and initial CSF and/or imaging findings. Aciclovir is a nucleoside analogue that is highly effective against HSV and other herpes viruses. Given intravenously at 10 mg/kg three times daily it reduces the risk of a fatal outcome from approximately 70% to less than 20%.19 Renal function should be monitored closely, and adequate hydration maintained, because of the rare risk of renal failure. Other rare side effects include local inflammation, hepatitis and bone marrow failure. Although the original aciclovir trials were for 10 days’ treatment, most neurologists would continue treatment for 14 or 21 days, especially in children with proven HSV encephalitis, because of the risk of relapse after 10 days.20 Some advocate repeating the CSF examination at the end of treatment and continuing with aciclovir if HSV is still detected. This approach is being evaluated by the American Collaborative Antiviral Study Group, which is assessing the prognostic value of quantitative PCR detection of viral DNA at the end of 3 weeks’ treatment, and prolonged high dose oral valaciclovir for 3 months. If the initial CSF PCR is negative for HSV, but other features are consistent with HSV encephalitis, then the aciclovir should not be stopped, because false negatives can occur, particularly early on.21 In such patients the LP should be repeated, and treatment

Table 5

be performed if there is any uncertainty. The EEG may help with the diagnosis in HSV encephalitis (see above). Seizures should be managed with intravenous phenytoin or phenobarbitone. Usually a child is maintained on one of these anticonvulsants for a minimum of 6 weeks following the acute illness. Intracranial pressure should be reduced by nursing the patient with their head elevated to 30°, keeping the head straight and keeping the patient as still as possible. The patient should be ventilated to keep a low pCO2 and bolus doses of mannitol should be given. The risk of deep venous thrombosis/pulmonary embolus should be reduced with TED stockings and prophylactic heparin; the risk of pressure sores reduced with appropriate mattresses

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Figure 2 MRI (T2 axial view) showing high signal if left temporal lobe in HSV type 1 encephalitis.

continued for at least 10 days. However, if a definitive alternative diagnosis has become apparent, or it seems very unlikely that the patient has VE, then it is reasonable to stop aciclovir.

Figure 3 MRI (coronal FLAIR) showing high signal in left temporal lobe in HSV type 1 encephalitis.

in other viral CNS infections. In VZV encephalitis steroids are used alongside aciclovir because of the strong vasculitic component of the disease. Severe HHV-6 disease is treated with ganciclovir or foscarnet, and plecornaril is used for severe EV infections. Interferon-alpha has been used in WNV and other flavivirus infections, but an RCT in JEV showed that it was not effective.24

Oral valaciclovir In a proven case of HSV encephalitis or if HSV encephalitis is strongly suspected, it may be reasonable to convert to oral valaciclovir if ongoing intravenous treatment is proving difficult (e.g. in a child who is now fully conscious).22 However, we would only consider this after the first 10 days of intravenous treatment. Occasionally, therefore, a child may require either a long line or central line to be inserted under general anaesthetic to complete a full course of treatment. Valaciclovir is an ester of aciclovir, which is converted to aciclovir after absorption, and has good oral bioavailability. Oral aciclovir should not be used in HSV encephalitis, because the levels achieved in the CSF are not high enough.

Management in the recovery period Children may require a prolonged period of rehabilitation both as an inpatient and as an outpatient. Ideally, this should be with a tertiary neurorehabilitation team. In our centre, we have a multidisciplinary acute brain injury team, consisting of paediatric neurologists, community paediatricians, neurophysiotherapists, occupational therapists, speech and language therapists, neuropsychologist and specialist teaching staff, that makes a full assessment and delivers a package of treatments and therapies for rehabilitation. It continues to be involved as children are re-integrated back to their local teams and will liaise with local services and schools to ensure the child has the best ongoing management (see Useful websites and further reading). Neurocognitive impairments are common after VE, including change in memory, perception and executive function skills, such as organizing and planning. These changes are most noticeable in older children and can make re-integration back into school very difficult. Before discharge a full neuropsychiatric assessment should be performed, including cognitive function, intelligence, memory and speech assessment, because this will help

Other treatments to consider Antibiotic treatment with a cephalosporin is usually given in children until a proven viral cause is identified. It is wise to treat until the blood and CSF cultures are known to be negative. In patients with brain swelling, corticosteroids and mannitol are often used to control RICP. A recent trial suggests steroids may be beneficial in adults with HSV encephalitis whether or not there is marked swelling.23 In patients with severe brain swelling, decompressive hemicraniectomy is sometimes ­performed. Other antiviral and immunomodulatory treatment Except for HSV encephalitis, there are few large randomized controlled trials (RCTs) assessing the efficacy of antiviral treatments

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Figure 4 EEG showing left sided periodic discharges every 2 seconds in HSV type 1 encephalitis.

the morbidity remains high.5 Poor prognostic factors include reduced GCS on admission and delays between hospitalization and starting aciclovir treatment (especially delays of greater than 2 days).26 Two-thirds of survivors have significant neuropsychiatric sequelae, including memory impairment (69%), personality and behavioural change (45%), dysphasia (41%) and epilepsy (up to 25%).27

determine the extent of any damage and identify where help is needed. Regular outpatient assessment following VE is important. Behavioural and psychiatric disturbances are common and may include depression, attention deficit hyperactivity disorder, aggressive behaviour or disinhibition. A referral to the local child and adolescent psychiatry team may be necessary. Memory difficulties can be an especially important problem in HSV encephalitis. A range of practical approaches can help to overcome these difficulties; these include simple measures such as the child keeping a notebook and diary, having a ­ communication book for school, labelling items around the house and leaving messages as reminders. For older children and adolescents, more sophisticated aids may be helpful, including a neuropage system (www.neuropage.nhs.uk), which sends pager reminder messages throughout the day. Excellent support and advice can be obtained from patient support groups, such as the encephalitis society (www.encephalitis.info). Other disabilities in the recovery period or afterwards include post-encephalitic seizures. Following VE, epilepsy is more likely in children who had recurrent seizures, status epilepticus, severe disturbance of consciousness, focal neurological signs or who deteriorated during hospital admission.25 If seizures return, then a more appropriate long term anticonvulsant can be chosen, such as carbemazepine or lamotrigine.

Summary Although VE is relatively uncommon in children in the UK, early recognition and appropriate investigation and management is essential, because of the devastating nature of the ­condition. In the UK, HSV-1 is the commonest cause and treatment with intravenous aciclovir for at least 14 days is now the standard management. Diagnostic techniques and areas within the management have improved (neurointensive care and rehabilitation). Despite these improvements, many long term sequelae are common. Therefore, although it is uncommon, VE is a devastating condition for children and their families and the personal and financial costs are high. It is therefore very important that VE is recognized and managed appropriately, and that paediatricians are up to date with recent developments and follow a rational approach to investigation and treatment.

Prognostic factors and outcome Funding

Although with aciclovir treatment the mortality of HSV encephalitis has decreased from about 70% to about 20%,

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TS is a UK Medical Research Council Senior Clinical Fellow. ◆ 14

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References 1 Koskiniemi M, Korppi M, Mustonen K, et al. Epidemiology of encephalitis in children. A prospective multicentre study. Eur J Pediatr 1997; 156: 541–545. 2 Solomon T, Hart I, Beeching N. Viral encephalitis: a clinician’s guide. Pract Neurol 2007; 7: 288–305. 3 Univeristy of Liverpool. www.liv.ac.uk/braininfections 4 Kennedy PG. Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 2004; 75(suppl 1): i10–15. 5 Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis 2002; 13: 6–11. 6 Esiri MM. Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci 1982; 54: 209–226. 7 Kumar S, Kumar S, Kohlhoff SA. Recurrent HSV-2 meningitis in a 9-year-old girl. Scand J Infect Dis 2006; 38: 570–572. 8 Chua KB, Goh KJ, Wong KT, et al. Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet 1999; 354: 1257–1259. 9 McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 2002; 26: 91–107. 10 Fodor PA, Levin MJ, Weinberg A, et al. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology 1998; 51: 554–559. 11 Kneen R, Solomon T, Appleton R. The role of lumbar puncture in suspected CNS infection - a disappearing skill? Arch Dis Child 2002; 87: 181–183. 12 Kneen R, Solomon T, Appleton R. The role of lumbar puncture in children with suspected central nervous system infection. BMC Pediatr 2002; 2: 8. 13 Chataway J, Davies NW, Farmer S, et al. Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests. QJM 2004; 97: 325–330. 14 Jeffery KJ, Read SJ, Peto TE, et al. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet 1997; 349: 313–317. 15 Cinque P, Cleator GM, Weber T, et al. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry 1996; 61: 339–345. 16 Tien RD, Felsberg GJ, Osumi AK. Herpesvirus infections of the CNS: MR findings. AJR Am J Roentgenol 1993; 161: 167–176. 17 McCabe K, Tyler K, Tanabe J. Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes simplex encephalitis. Neurology 2003; 61: 1015–1016. 18 Lin JJ, Lin KL, Wang HS, et al. Analysis of status epilepticus related presumed encephalitis in children. Eur J Paediatr Neurol 2007 Jun 19 (epub ahead of print). 19 Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314: 144–149. 20 Yamada S, Kameyama T, Nagaya S, et al. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry 2003; 74: 262–264. 21 Coren ME, Buchdahl RM, Cowan FM, et al. Imaging and laboratory investigation in herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 1999; 67: 243–245.

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22 Chan PK, Chow PC, Peiris JS, et al. Use of oral valaciclovir in a 12-year-old boy with herpes simplex encephalitis. Hong Kong Med J 2000; 6: 119–21. 23 Kamei S, Sekizawa T, Shiota H, et al. Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry 2005; 76: 1544–1549. 24 Solomon T, Dung NM, Wills B, et al. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet 2003; 361: 821–826. 25 Lee WT, Yu TW, Chang WC, et al. Risk factors for postencephalitic epilepsy in children: A hospital-based study in Taiwan. Eur J Paediatr Neurol 2007; 11: 302–309. 26 Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet 1984; 2: 707–711. 27 McGrath N, Anderson NE, Croxson MC, et al. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997; 63: 321–326. 28 Solomon T, Whitley RJ. Arthropod-borne viral encephalitides. In: Scheld M, Whitley RJ, Marra C, eds. Infections of the Central Nervous System, 2nd Edn. Philadelphia: Lippincott, Williams and Wilkins, 2004.

Useful websites and further reading Appleton R, Baldwin T, eds. Management of brain injured children. 2nd Edn. Oxford: OUP, 2006, Book with useful information about rehabilitation of children with acute brain injury from any cause. Encephalitis Society. Can provide support for patients and their families. Also provides teaching, training and educational materials for health care professionals. www.encephalitis.info Health protection Agency funded Prospective Study of Viral Encephalitis. www.hpa.org.uk/infections/topics%5Faz/encephalitis/study.htm Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes 2004; 11(suppl 2): 65A–76A. Review of neonatal herpes simplex encephalitis.

Practice points • Viral encephalitis (VE) is uncommon but suspected CNS infections are not. Paediatricians should have a rational approach to investigation and management of children with suspected CNS infection • A definitive diagnosis is made in approximately 30% of cases of VE. This figure can be improved by taking advice from a virologist or paediatric neurologist • A lumbar puncture is essential in patients with suspected VE. It may be delayed in patients with suspected brain shift. Results from CSF analysis are useful even after treatment has been started. For HSV encephalitis, PCR remains positive in about 80% of patients even 1 week after starting antiviral therapy • The commonest cause of VE in the UK is HSV-1. Globally the commonest cause is JEV • The mortality and morbidity from VE are high. Both have decreased for HSV encephalitis since aciclovir became the

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Acknowledgments

standard treatment. However, specific treatments are not available for most other types of VE • The incidence of VE may be increasing. Global travel and environmental changes may mean we see an increase in new outbreaks of VE in the future

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We thank Dr Nick Beeching and Dr Ian Hart for helpful ­discussions, Mrs Margaret Beirne and Dr Richard Appleton for the EEG and Dr Lawrence Abernethy for CT and MRI scan images.

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Evaluation of the floppy infant

reflex, whilst postural tone is measured by the response of the muscle to a sustained low-intensity stretch, as illustrated by the body’s ability to maintain posture against the force of gravity.

Vasantha Gowda

Clinical appearance

Jeremy Parr

Some features are common to all floppy infants regardless of the aetiology and location of the abnormality. A child is generally said to be floppy if he/she assumes a frog-like posture, is unable to maintain normal posture against gravity, exhibits diminished resistance to passive movements and has an excessive range of joint mobility. Table 1 lists some of the clinical signs with which a floppy infant may present; these features may or may not co­exist in the same infant.

Sandeep Jayawant

Abstract This review outlines a clinical approach to the evaluation of the floppy infant. Attention is drawn to the varied manner in which the condition can present, and emphasis is placed upon a detailed assessment of characteristic clinical findings. A distinction is drawn between central and peripheral causes for hypotonia. Guidance is given regarding the importance of evaluating the child for signs of weakness, which is an important marker of neuromuscular pathology. Reference is made to situations where peripheral pathology may mimic central disorders. A diagnostic algorithm is outlined for the investigation of neuromuscular disorders, and reference is made to the discrepancy in findings that often exists between electromyography and muscle biopsy findings. Attention is drawn to available therapeutic options, as well as the importance of addressing ethical issues, which become of particular importance once a diagnosis is reached.

Common modes of presentation The clinical consequences of hypotonia and/or weakness may be evident even in antenatal life.1 Specific questions in the history should address whether fetal movements were normal, as well as whether there was evidence of polyhydramnios. In the neonatal period, the manner of presentation depends on the severity of the condition. This ranges from the consequences of fetal immobilization, such as hip dislocation, arthrogryposis, talipes and flexion deformity of all limbs, to respiratory and feeding difficulties (slow feeding, recurrent choking or aspiration episodes). Later in infancy, hypotonia may be more obvious once delayed achievement of motor milestones becomes evident, with or without accompanying delay in other areas of development.

Keywords hypotonia; neuromuscular; neuropathy Clinical confirmation of hypotonia Once the suspicion of hypotonia has been raised, the evaluation of the floppy infant should proceed by searching for those clinical signs that corroborate the diagnosis (Figures 1 and 2).

Introduction and definition The word ‘floppy’ can be used to mean: • decrease in muscle tone (hypotonia); • decrease in muscle power (weakness); • ligamentous laxity and increased range of joint mobility. Strictly speaking, the term ‘floppy’ should be used to describe hypotonia. The interconnection between tone, muscle strength and joint mobility can be appreciated through a consideration of the definition of tone – the resistance to passive movement around a joint. Phasic tone is assessed by the response of the muscle to a rapid stretch, illustrated classically by a tendon

Diagnostic approach The initial approach to a floppy infant is to determine whether the problem is of central or peripheral origin. This is of crucial importance when forming a plan for diagnostic investigations. As a general rule, an attempt is made to gauge whether there

Clinical signs in a floppy infant • Observation of a ‘frog-leg’ posture. This generally implies reduced spontaneous movement, with the legs fully abducted and arms lying beside the body either extended or flexed • Significant head lag on traction or pull-to-sit manoeuvre and excessively rounded back when sitting (>33 weeks) • Rag-doll posture on ventral suspension • Vertical suspension test – feeling of ‘slipping through the hands’ when the infant is held under the arms • Various associated examination findings such as flat occiput or congenital dislocation of the hips, arthrogryposis

Vasantha Gowda MBBS MRCP is a Specialist Registrar, Department of Paediatric Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Q1

Jeremy Parr MBChB MD MRCPCH is a Clinical Lecturer, Department of Paediatric Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Sandeep Jayawant MD FRCP FRCPCH is a Consultant Paediatric Neurologist, Department of Paediatric Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.

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Table 1

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Clinical features suggestive of hypotonia of central origin • Social and cognitive impairment in addition to motor delay • Dysmorphic features implying a syndrome or other organ malformations sometimes implying a syndrome • Fisting of hands • Normal or brisk tendon reflexes • Features of pseudobulbar palsy, brisk jaw jerk, crossed adductor response or scissoring on vertical suspension • Features that may suggest an underlying spinal dysraphism • History suggestive of hypoxic-ischaemic encephalopathy, birth trauma or symptomatic hypoglycaemia • Seizures Table 2

Table 3 shows features in the history and clinical examination that indicate the hypotonia and/or weakness are more likely due to peripheral (neuromuscular) causes. During infancy, formal testing for both tone and weakness is more difficult and relies more heavily on clinical evaluation as well as the search for ­corroborating risk factors. In some conditions, both central and peripheral hypotonia may coexist (Table 4). Once the decision about central or peripheral (neuromuscular) aetiology has been made, investigations are directed accordingly to identify the specific condition causing the hypotonia. Tables 5 and 6 list some of the causes of hypotonia and/or weakness resulting from central and peripheral (neuromuscular) causes, ­respectively.

Figure 1 Head lag.

is a significant element of weakness. Paralytic hypotonia with ­significant weakness suggests a peripheral neuromuscular problem, whereas non-paralytic hypotonia without significant weakness points to a central cause which may be neurological, genetic, syndromic or metabolic. A central cause is suggested by clinical features as described in Table 2. The presence of these findings does not, however, exclude a peripheral aetiology of weakness. In some cases features suggesting both central and peripheral aetiologies may be seen.

Indicators of peripheral hypotonia • Delay in motor milestones with relative normality of social and cognitive development • Family history of neuromuscular disorders/maternal myotonia • Reduced or absent spontaneous antigravity movements, reduced or absent deep tendon jerks and increased range of joint mobility • Frog-leg posture or ‘jug-handle’ posture of arms in association with marked paucity of spontaneous movement • Myopathic facies (open mouth with tented upper lip, poor lip seal when sucking, lack of facial expression, ptosis and restricted ocular movements) • Muscle fasciculation (rarely seen but of diagnostic importance when recognized) • Other corroborative evidence including muscle atrophy, muscle hypertrophy and absent or depressed deep tendon reflexes

Figure 2 Classic posture in hypotonia.

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Table 3

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Conditions where central and peripheral hypotonia may coexist

Causes of paralytic/neuromuscular hypotonia Spinal muscular atrophy Paralytic poliomyelitis Neuropathies • Hereditary motor-sensory neuropathy • Congenital hypomyelinating neuropathy • Acute demyelinating polyneuropathy

• Familial dysautonomia • Hypoxic–ischaemic encephalopathy • Infantile neuroaxonal degeneration • Lipid storage diseases • Lysosomal disorders • Mitochondrial disorders • Perinatal asphyxia secondary to motor unit disease

Neuromuscular junction problems • Botulism • Transient neonatal myasthenia • Autoimmune myasthenia • Congenital myasthenic syndromes

Table 4

Investigations where central hypotonia is suspected The range of investigations that may yield diagnostic clues in the clinical setting of non-paralytic/central hypotonia are listed in Table 7. The diagnosis of central hypotonia attributable to hypoxic-ischaemic encephalopathy is based upon an appropriate clinical history along with concordant imaging studies of the brain. Metabolic disorders are rare and despite extensive investigations the diagnostic yield may be quite low.

Muscular disorders • Congenital myopathies (nemaline rod myopathy, myotubular myopathies, central core disease, minicore disease, etc) • Congenital muscular dystrophies (CMD) (Walker-Warburg, Fukuyama, muscle-eye-brain disease, merosin-positive CMD, etc) • Congenital myasthenic syndromes • Congenital myotonic dystrophy • Metabolic myopathies (acid maltase deficiency, phosphorylase deficiency, mitochondrial myopathy • Endocrine myopathies (hypothyroidism)

Investigations where peripheral hypotonia is suspected Investigations likely to yield diagnostic clues in cases where paralytic/neuromuscular hypotonia is suspected are listed in Table 8. Myotonic dystrophy is usually suspected on the basis of known family history or recognition of the disorder in an affected mother, and can be confirmed by testing for the expanded CTG

Table 6

trinucleotide repeat sequence on chromosome 19q13.2–q13.3. In the absence of a diagnosis of myotonic dystrophy, we support the early use of electromyography (EMG)/nerve conduction studies (NCS) when a peripheral cause is likely.2 Areflexia, decreased limb movements and denervation on EMG should prompt investigation for anterior horn cell disorders (­spinal

Conditions associated with central (non-paralytic) hypotonia Acute encephalopathies • Birth trauma • Hypoxic-ischaemic encephalopathy • Hypoglycaemia

Investigations in cases where a central cause for hypotonia is suspected

Chronic encephalopathies • Cerebral malformations • Inborn errors of metabolism (mucopolysaccharidoses, aminoacidurias, organic acidurias, lipidoses, glycogen storage diseases, Menkes syndrome) • Chromosomal disorders (Prader-Willi syndrome, trisomy 21) • Genetic disorders (familial dysautonomia, Lowe syndrome) • Peroxisomal disorders (neonatal adrenoleukodystrophy, Zellweger syndrome) Endocrine (hypothyroidism) • Metabolic (rickets, renal tubular acidosis) •

• Serum electrolytes, including calcium and phosphate, serum alkaline phosphatase, venous blood gas, thyroid function tests • Plasma copper/caeruloplasmin assay (as screening test for Menkes syndrome) • Chromosomal analysis (trisomy), testing for Prader-Willi syndrome(15q11–13) • Plasma amino acids and urine organic acids • Urine mucopolysaccharide screen (GAG) • Molecular/biochemical diagnosis of pro-collagen disorders • Very long chain fatty acids • Medical genetics opinion • Ophthalmology opinion • Brain imaging (CT/MRI)

Connective tissue disorders • Ehlers-Danlos syndrome • Osteogenesis imperfecta • Congenital ligamentous laxity • Benign congenital hypotonia Table 5

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Table 7

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Investigations of peripheral hypotonia

Useful EMG features in peripheral hypotonia

• Creatinine kinase • Lactate • EMG/NCS/repetitive nerve stimulation test • Muscle biopsy (histology, immunohistochemistry, electron microscopy, respiratory chain enzyme analysis) • Genetic testing (SMN gene deletion present in 95% of cases of spinal muscular atrophy type 1, myotonic dystrophy, congenital myasthenic syndromes) • Nerve biopsy (rarely) • Tensilon test

• EMG/NCS studies may distinguish between neurogenic, myopathic and myasthenic aetiologies for hypotonia • Neurogenic – large amplitude action potentials, reduced interference pattern, increased internal instability • Myopathic – small amplitude action potentials with increased interference pattern • Myotonic – increased insertional activity • Myasthenic – abnormal repetitive and single fibre studies Table 9

Table 8

usually inconclusive.5 In general, EMG and biopsy studies more often concur in denervation than myopathy. Classic EMG/NCS findings in myopathic and neurogenic disorders are outlined in Table 9. Recent advances in the diagnosis of congenital myasthenic syndromes allow for DNA testing in some of the common syndromes where there is strong clinical suspicion, particularly in young children where accurate neurophysiology evidence is sometimes difficult to obtain.6

­ uscular atrophy), and can be confirmed by testing for the m homozygous deletion of exon 7 in the telomeric survival motor neurone gene.3 Failure to identify electrophysiological abnormalities should prompt testing for Prader-Willi syndrome. Arthrogryposis, feeding difficulties, recurrent apnoeic/choking episodes, ­ophthalmoplegia, ­ptosis and fatigability should prompt ­investigations for congenital myasthenic syndromes. Finally, muscle biopsy is recommended in neonates with weakness, even if needle EMG is normal (Figure 3). Care should, however, be taken in patient selection for muscle biopsy because of an increased risk of anaesthetic complications (postoperative respiratory failure and reactions to anaesthetic agents, particularly malignant hyperthermia and rhabdomyolysis). EMG studies are used as a supportive diagnostic tool in deciding whether there is true weakness due to neuromuscular disease, or hypotonia from causes in other systems or other parts of the nervous system, and whether the process is due to a myopathic, neuropathic or a denervating process.4 In general, EMG can be performed at any age, although some caution is required in the interpretation of results within the first 6–8 weeks of life, particularly if the baby was premature. Whilst severe myopathy or neuropathy is not usually difficult to diagnose on EMG, studies on cases of mild weakness are

Therapeutic approach Various aspects of function may be affected in a floppy infant. In most cases, supportive therapies are indicated. Few conditions have specific treatments. These include hypothyroidism (thyroxine), some types of congenital myasthenic syndromes (pyridostigmine or neostigmine) and rickets (vitamin D). Some metabolic disorders may respond to specific dietary modifications or enzyme replacement therapies. The mainstays of ­ treatment are outlined in Table 10.

Prognosis and prevention Rapid as well as accurate diagnosis of individual cases is vital in order to provide precise prognostic information. Ethical considerations, such as the appropriateness of cardiopulmonary

Left, muscle biopsy (histochemistry) and right, electron microscopy in nemaline rod myopathy (congenital myopathy). Figure 3

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4 Brett EM. Pediatric neurology. Edinburgh: Churchill Livingstone, 1997. 5 Russell JW, Afifi AK, Ross MA. Predictive value of electromyography in diagnosis and prognosis of the hypotonic infant. J Child Neurol 1992; 7: 387–389. 6 Parr JR, Jayawant S. Childhood myasthenia:clinical subtypes and practical management. Dev Med Child Neurol 2007; 49: 629–635.

Principles of management • Physiotherapy - stretches aimed at prevention of contractures • Occupational therapy - appliances, improvement of posture and function, facilitating activities of daily living • Prevention and correction of scoliosis • Evaluation and treatment of associated cardiac dysfunction • Respiratory support - assessment of requirement for invasive or non-invasive ventilation and/or tracheostomy • Feeding - nasogastric feeding, caloric supplementation, gastrostomy • Management of gastro-oesophageal reflux - medical or fundoplication • Orthopaedic intervention in setting of established or evolving joint contractures • Encouragement of overall development and stimulation of learning • Prevention (influenza and pneumococcal vaccination) and prompt treatment of respiratory infections

Recommended reading Dubowitz V. Muscle disorders in childhood. London: WB Saunders Company, 1995.

Practice points • Many neurological and non-neurological disorders can present with hypotonia • Central causes of hypotonia must be distinguished from those due to neuromuscular disease • Neuromuscular causes are usually characterized by the presence of significant weakness • Neurophysiological studies are a helpful initial investigation • Muscle biopsy is usually required to diagnose muscle disease • Some conditions can be diagnosed on genetic testing alone

Table 10

resuscitation in the event of cardiac arrest or acute respiratory failure, need to be addressed sensitively. Informed discussion around these issues requires detailed knowledge, where available, of specific conditions and, in particular, their presentation, clinical features, course and outcomes. Prenatal diagnosis using amniocentesis or chorionic villus sampling is often feasible if a definitive diagnosis has been reached in the index case. ◆

Recent developments • Recent advances in genetics have uncovered new conditions causing hypotonia and weakness such as congenital myasthenic syndromes and spinal muscular atrophy variants • Advances in immunohistochemistry, electron microscopy and genetics have led to a more specific diagnosis of myopathies • Some of these advances have allowed for specific therapeutic interventions, e.g. use of acetylcholinesterase inhibitors in some congenital myasthenic syndromes

References 1 Fenichel GM. Pediatric neurology. Philadelphia: WB Saunders Company, 2005. 2 Richer LP, Shevell MI, Miller SP. Diagnostic profile of neonatal hypotonia: an 11-year study. Pediatr Neurol 2001; 25: 32–37. 3 Nicole S, Diaz CC, Frugier T, et al. Spinal muscular atrophy: recent advances and future prospects. Muscle Nerve 2002; 26: 4–13.

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Recent developments in the management of Duchenne muscular dystrophy

Introduction Duchenne muscular dystrophy (DMD) affects 1 in every 3500 live male births. DMD is the first genetic condition for which the defect was identified by positional cloning. Approximately 65% of patients with DMD have intragenic out-of-frame (gross rearrangements) deletions and approximately 10% have duplications of one or more exons of the dystrophin gene.1 The remaining patients have point mutations or other smaller gene rearrangements (pure intronic deletions, insertions of repetitive sequences, splice site mutations). Depending on the type of mutation, there may be a severe reduction or absence of dystrophin in the muscle, resulting in DMD phenotype, or a partly functional truncated protein, resulting in the milder Becker muscular dystrophy (BMD).1 Dystrophin links the cytoskeleton to the extracellular matrix.1 Lack of dystrophin compromises this link, leading to muscle fibre degeneration. Dystrophin also appears to play a role in signal transduction, although this has a limited role in the pathogenesis of the muscle degeneration. The common presentation of DMD is with abnormal gait and difficulty in rising from the floor, which becomes clinically evident between the ages of 3 and 5 years. Progression of muscle weakness and contractures of the tendon Achilles (TA) leads to loss of walking at a mean age of 9.5 years. Wheelchair dependence is associated with progressive scoliosis. In untreated individuals, the leading cause of death is respiratory insufficiency in the late teens or early 20s. Approximately 80% of deaths are related to respiratory complications, while 20% succumb to dilated cardiomyopathy (DCM). Feeding difficulties and weight loss are common in the late stages of the disease. No curative treatment for DMD is known, but the quality of life and comfort of the patient can be improved by symptomatic physiotherapeutic and medical treatments.

Maria Kinali Adnan Y Manzur Francesco Muntoni

Abstract Duchenne muscular dystrophy (DMD) is the most common and severe childhood muscular dystrophy, resulting in progressive muscle weakness and wasting, disability and decreased survival. Although the molecular defect in DMD is known, no curative treatment is available. The treatment options of glucocorticoid corticosteroids and supportive measures, such as ventilation and management of cardiac insufficiency, have become accepted clinical practice in the last decade, and these are of major interest to the paediatrician as they have significantly changed the course of the disease in treated individuals. This has implications not only for the affected individual and his family, but also for the medical and social sectors to provide transition to adult medical services and for provision of suitable employment, and social care. Several experimental therapeutic strategies, including cell and gene therapy, are promising, with encouraging results in relevant animal models and in cultured human cells. As a number of approaches are in early clinical trials, expectations are raised of their impact as a cure for DMD; nevertheless, it is not realistic to expect that these approaches will have a substantial impact on disease course in the short term. While waiting for a curative therapy to become available, symptomatic and palliative treatment is essential to enhance the patient’s quality of life. This review addresses the advances in these therapies aimed at improving function and quality of life in patients with DMD, and the current status of ­research into the DMD experimental therapies.

Symptomatic treatment modalities Physiotherapy Physiotherapy to promote walking and prevent joint deformities remains the mainstay of treatment. Prevention/control of lower limb contractures is achieved by a regular passive stretching of the TA and the use of night splints once the ankles cannot be dorsiflexed beyond the neutral position. Exercise programmes, such as swimming, are recommended, while activity against resistance is not. Detailed recommendations for exercise and physiotherapy are available.2

Keywords Duchenne muscular dystrophy; management; therapy

Prolongation of walking with orthoses Rehabilitation in knee–ankle–foot orthoses (KAFOs) is effective in prolonging walking for an average of 18 months to 2 years. Prolongation of walking beyond 13 years of age protects against rapidly progressive scoliosis.3 KAFOs are offered to boys with DMD at the end of independent ambulation, i.e. when they can take only a few steps with/without assistance. The technique involves custom-built KAFOs and surgical release of the TA, or serial casting to reduce ankle contracture and allow fitting of KAFOs. Regular review at a centre with rehabilitation facilities has the advantages of psychological preparation of the child and family for loss of walking, and choosing the appropriate timing for intervention.

Maria Kinali MD MRCPCH is a Senior Clinical Research Fellow at the Dubowitz Neuromuscular Centre, Department of Paediatrics, Division of Medicine, Hammersmith Campus, Imperial College, London. Adnan Y Manzur DCH FRCPCH is a Consultant Paediatrician at the Dubowitz Neuromuscular Centre, Department of Paediatrics, Division of Medicine, Hammersmith Campus, Imperial College, London. Francesco Muntoni MD FRCPCH FMed Scie is a Professor of Paediatric Neurology at the Dubowitz Neuromuscular Centre, Department of Paediatrics, Division of Medicine, Hammersmith Campus, Imperial College, London.

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Beta-2 agonists: beta-2 adrenergic agonists have been shown to induce muscle hypertrophy and prevent atrophy after physical and biochemical insults in animal studies. A 12-week RCT showed that albuterol increased muscle strength in knee extensors and flexors in nine ambulant patients with DMD.8 These results need confirmation in a larger RCT. The safety of albuterol on increasing heart rate, especially in those with concurrent DCM, remains to be addressed.

Pharmacotherapy Corticosteroids: of the pharmacological agents tried in DMD, glucocorticoid corticosteroids are the most effective. The Cochrane systematic review of the glucocorticoids in DMD4 and European Neuromuscular Centre Steroids in DMD workshop report5 review the evidence and summarize the benefits, risks, research and clinical aspects of this treatment. Randomized controlled trials (RCT) have shown that treatment with prednisolone can stabilize strength and function for 6 months to 2 years.4 Prednisolone has been the most widely used medication and the starting dose is 0.75 mg/kg/day. Non-­randomized studies with prednisolone or deflazacort have documented prolongation of walking ability, preservation of respiratory function as indicated by forced vital capacity (FVC) and reduction in the incidence of scoliosis and cardiomyopathy in boys with DMD who tolerated long term daily doses of corticosteroids. The daily steroid regimens have significant side effects, notably vertebral fractures in approximately a third of patients treated long term. In order to lessen the adverse effects, Dubowitz recommended an intermittent regimen of prednisolone; a 6-month RCT of prednisolone 0.75 mg/kg/day for the first 10 days of every month demonstrated slowing of functional deterioration. Despite the uncertainties regarding the long term safety of corticosteroids in DMD, they have been shown to alter the natural history in relation to ambulation, cardiomyopathy, respiratory function and scoliosis. Corticosteroids should be preferably commenced in all early ambulant cases (4–7 years) and in most older ambulant children, unless contraindicated. Treatment needs to be monitored for benefit, adverse effects and dose adjustment. The optimal starting dose of prednisone (0.75 mg/kg/day) is often not tolerated in the long term and, over the course of years, the dose often has to be decreased. Follow-up in a specialist centre allows for appropriate monitoring, dosing and management of adverse effects. Optimizing bone health in corticosteroid-treated patients includes dietary advice regarding calcium and vitamin D, and supplementation if plasma vitamin D levels are low.6 There is currently no consensus on the prophylactic use of bisphosphonates, but they are indicated for treatment of vertebral fractures.

Management of respiratory complications The teenage years in DMD are marked by decreased respiratory reserve and sleep hypoventilation, which is a sequel of respiratory muscle weakness and rapid eye movement (REM) sleep related hypoxemic dips. The spectrum of symptoms includes morning drowsiness, poor appetite, headaches, nausea, fatigue, tiredness, dysthymia, poor concentration at school, failure to thrive, reduced coughing ability or overt respiratory failure in the course of ‘minor respiratory infections’. In untreated patients who have become hypercapnic, the survival is less than a year.9 Until recent decades, this signified imminent demise, as the only option to prolong life was the use of a mechanical ventilator through tracheostomy; this was limited by the complex ethical issues of invasive ventilation of patients with totally incapacitating and incurable disease with no option for a ‘normal’ death. In recent years, domiciliary non-invasive ventilation (NIV) has proven effective in symptom relief and prolonging survival. The patient’s breathing at night is augmented with breaths delivered by a compact, portable ventilator with a snugly fitting facial or nose mask. NIV corrects sleep hypoventilation without significant noise, encroachment on living space or restriction of travel, and together with the use of cough-assist devices, can extend survival to the average mid-20s and in rare cases to the fourth decade.9 Because of these findings, many physicians have argued that denying NIV to hypercapnic patients with DMD is unethical. Regular monitoring for symptoms of sleep hypoventilation, FVC and overnight sleep studies when the FVC falls below 60% allow for timely initiation of NIV. Gradual initiation of NIV in individuals with nocturnal hypercapnia but daytime normocapnia is advantageous, as waiting for daytime ventilatory failure exposes patients to minor chest infections and uncontrolled decompensation.10

Creatine: a dietary component in meat eaters, is also synthesized endogenously and is stored primarily in skeletal muscle. Creatine in the muscle is converted to phosphocreatine to build and provide energy in the form of adenosine triphosphate. Creatine may enhance the performance of high-­intensity, short-duration exercise but is not useful in endurance sports. Creatine pre-­treatment of mdx mice muscle cell cultures increased phosphocreatine ­levels, myotube formation and survival. A RCT of creatine supplementation in DMD has failed, however, to show any significant improvement in strength and function.7

Management of cardiac complications DCM occurs in up to 90% of boys with DMD aged ≥18 years. DCM becomes symptomatic only in a minority and is the cause of death in 20%. It is likely that DCM may manifest in a larger proportion of individuals in whom NIV prevents respiratory-related morbidity. The optimal timing of introducing therapy for DCM remains an unresolved issue. Duboc et al11 have shown that early treatment with perindopril delayed the onset and progression of left ventricular dysfunction. There is a debate in the literature as to whether to treat a complication that is often asymptomatic for a long time before deteriorating into clear-cut cardiac failure. Current evidence on other forms of DCM shows early treatment to be clearly superior to late therapy.12 While awaiting the results of RCTs, several consensus documents have been prepared which recommend the use of ­angiotensin converting enzyme (ACE) inhibitors, beta blockers and diuretics in patients with early cardiomyopathy.13 Aggravation of cardiac failure by nocturnal hypoventilation should be looked for and treated.

Coenzyme Q10 and antioxidants: coenzyme Q10 (CoQ10) is ­synthesized endogenously, absorbed by the gastrointestinal system and then bound in the inner mitochondrial membrane regulating respiratory chain effects. Previous double blind trials have shown low efficacy, making it difficult to rule out any disease modifying effect. A phase III clinical trial is currently assessing the effect of CoQ10 (serum level greater than 2.5 μg/ml) and prednisolone (0.75 mg/kg/day) in wheelchair-dependent patients with DMD (http://www.clinicaltrials.gov/).

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The risk of cardiac involvement in carriers of DMD is approximately 10%, and this may occur in the absence of muscle ­weakness. Genetic counselling should include informing carriers of the cardiac risks, and their surveillance and treatment planned for.

Experimental therapies The last decade has seen major advances in understanding of the molecular genetics and pathogenesis of the muscular dystrophies, and this in turn has raised expectation of a curative treatment with gene therapy.

Management of scoliosis Scoliosis usually manifests after loss of walking, shows rapid progression coincident with the pubertal growth spurt and has a negative impact on respiratory function, feeding, seating and comfort. Scoliosis and age to which walking is preserved are interrelated, with much lower incidence in boys who have walked for longer, having used steroids and/or KAFOs.14 A spinal brace does not prevent progression of scoliosis, but may be useful in postural management. Surgical spinal fusion is indicated when the spinal curve is progressing, and the optimum time for making the decision is when the range of the curve’s Cobb angle is 20–40°.15 The decision to offer surgery needs input from the multidisciplinary team, and pre-operative assessment is essential to ensure that the operation is safe and a time chosen for surgery when the FVC is greater than 30% predicted for height and the cardiac function, as ­demonstrated by echocardiogram, is good. Spinal surgery can be performed when the FVC is between 20% and 30%, but the risks are greater and this should be undertaken in specialized centres.

Animal models Two naturally occurring animal models for DMD have been crucial in testing the safety and efficacy of gene therapy and other new pharmacotherapies. The dystrophic golden retriever dog (GRMD) has a point mutation, which induces exon skipping, muscle wasting and weakness, contractures and decreased survival akin to the human disease. The mdx mouse has a stop codon in exon 23, resulting in dystrophin-deficient muscle fibres, but phenotypically the mouse is not weak and its survival is only minimally limited compared to wild type. Drugs affecting fibrosis: blocking endogenous muscle calcium proteases and transforming growth factor β Transforming growth factor β (TGF β) inhibits terminal differentiation of human cultured myoblasts in vitro. Increased activity of TGF β leads to failed regeneration in mdx mice.19 Losartan (an angiotensin II type 1 receptor antagonist) antagonizes TGF β and has been shown to ameliorate the signs of dystrophy in mdx mice. This has inspired hope that use of a common drug such as losartan could potentially be effective for all cases of DMD; a RCT of losartan is currently planned in DMD.

Nutritional aspects The spectrum of nutritional difficulties includes initial presentation with failure to thrive, obesity during the late ambulant phase, especially in corticosteroid treated individuals, and wasting in the spinal surgery postoperative period and the late teenage years. All patients with DMD should be given dietary advice to avoid obesity, which has negative implications for mobility, especially when the patient is treated with daily ­steroids. Young adults with DMD may have chewing and swallowing difficulties, choking and fear of choking, and failure to thrive. Appropriate facilities for weighing wheelchair-dependent adolescent patients should be available in the clinics to allow for regular weight monitoring. Patients with failure to thrive and/or swallowing difficulties benefit from a dietetic and a speech and language therapist’s assessment as nutritional supplementation and observation of mealtimes and swallowing videofluoroscopy allow further advice about postural management, feeding aids or gastrostomy insertion.16

Genetic approaches Currently, adeno-associated virus (AAV) is the vector of choice for gene therapy of muscular dystrophy. AAV is a small, non-enveloped, single-stranded DNA virus, which requires co-infection with a second ‘helper’ virus for replication. The main advantage of AAV resides in its efficiency in transducing skeletal and cardiac muscles after intravenous injection. Wild-type AAV does not cause any human disease and only induces a mild immune response. There are several challenges of the AAV gene therapy approach. The small genome size carried by the AAV is a drawback for the insertion of large transgenes such as dystrophin. Removal of the non-essential portion of the dystrophin gene has allowed ‘minigenes’ and smaller ‘microdystrophins’ to be engineered but their effectiveness remains under investigation, particularly in larger animal models. Stimulation of an undesirable immune response and toxicity can be minimized by using muscle-specific promoters to restrict expression to target muscle cells. As high viral load is necessary, substantial advances in vector production and muscle transduction efficiency with recently developed serotypes to lower AAV doses are important20 before use in future clinical trials. Other hurdles are that viral vectors rarely integrate into chromosomes and are lost from cells contributing to muscle regeneration following multiple cell divisions, and the concern of potential immune response to the vector and/or transgene. Recombinant AAV vectors do not contain any viral genes, but the vector capsid proteins are capable of inducing humoral immune responses in animals, a major obstacle to subsequent treatments. Transient immune suppression strategies to prevent any cell-mediated response to the vector itself are being explored,21 in addition to the possibility of

Survival and transition of care It was common practice for the paediatrician to stay in charge of the medical care of patients with DMD because the limited survival into the third decade of life in only a minority of patients was considered not to justify the transfer of care to the adult medical teams with the attendant psychological impact on the young person and family. This resulted in lack of formal arrangements for transition of care to the adult teams. The improvements in general care in the 1970s and the frequent provision of NIV from the 1990s, has improved the mean survival in the UK to 27 years17 and further prolongation of survival is anticipated as a result of corticosteroid treatment. This underlines the need for development of good transition protocols and, in particular, improvement in rehabilitation and social services for the adult with DMD.18

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using different serotypes for the subsequent administrations. It remains to be seen whether human dystrophin will provoke an immune response in patients with DMD.

Modification of dystrophin mRNA splicing: antisense oligomers and exon skipping trials Antisense oligonucleotides or oligomers (AOs) are research tools used to knock down target gene expression. More recently, AOs have also been used to redirect splicing and induce exon skipping. The dystrophin gene is an ideal target for such a strategy: most individuals with DMD have out-of-frame deletions or duplications, which result in non-functional dystrophin proteins, while deletions that maintain the open reading frame give rise to semi-functional dystrophins and milder phenotypes (BMD). Internally-truncated dystrophins are also expressed in so-called ‘revertant fibres’ – individual dystrophin-positive fibres found in 50% of DMD patients and in mdx mice.1 These revertant fibres arise via aberrant splicing and unexpected skipping of exons, which flank the deleted exons; this results in restoration of the open reading frame. In DMD it is possible to target an exon which flanks an out-of-frame deletion so that the reading frame can be restored and dystrophin production allowed. This can be achieved by AOs which prevent the normal splicing of genes by masking crucial areas of the messenger RNA during the splicing process. The early proof of concept studies were done in cell cultures of the mdx mouse and subsequently in DMD cells. More recently, the direct injection of AOs into the muscle of mdx mice resulted in robust restoration of dystrophin expression at the sarcolemma.28 Systemic administration of AOs in the mdx mouse also resulted in appreciable induction of exon skipping, and repeated intravenous administration of AOs resulted in functional levels of dystrophin expression in body-wide skeletal muscles of the mdx mouse, with corresponding improvement in muscle function.29 Despite these encouraging results, there are several limitations of AOs. First, different deletions will require different AOs and, second, the treatment is not permanent but limited to the period in which the AO persists in the tissue. AO treatment will therefore require repeated administrations for the entire life of the patient with DMD, and whether this will be associated with any toxicity is not known. AOs nevertheless have a fairly good safety profile from data available on human trials. Two European consortia in the Netherlands (http://prosensa.eu/news/ news_may10_06.pdf) and the UK (http://clinicaltrials.gov/ct/gui/ show/NCT00159250?order=1) are currently testing the safety and local efficacy of intramuscularly administered AOs and results are expected in late 2007. These results will inform the feasibility of future systemic delivery studies, which are planned for 2008.

Utrophin upregulation Utrophin, a protein homologous to dystrophin,22 binds to the dystrophin–glycoprotein complex. In normal adults, utrophin is localized at the post-synaptic membranes of the neuromuscular junction, peripheral nerves and vascular bed of their skeletal muscles. Utrophin is virtually absent at the sarcolemma of mature muscle fibres but is highly expressed in the sarcolemma of fetal and regenerating fibres and represents another indirect marker of dystrophy. Utrophin can prevent dystrophic pathology in the transgenic mdx mouse, leading to the hypothesis that utrophin might be capable of supplanting dystrophin, without provoking an immune response and possibly reducing the disease severity.22 The UK company VASTox recently discovered a drug compound VOXC1100, which upregulates utrophin, and clinical trials are planned. The wide applicability of such a technique holds promise for different muscular dystrophies; however, potential response differences between humans and the mdx mouse will have to be addressed first. Cell transplantation Transplantation of myoblasts has demonstrated negative or very modest results in DMD. The proof of principle came from studies in the mdx mouse, which resulted in dystrophin expression. The main limitation of this approach is that transplanted cells are unable to migrate following direct injection, so any effect is limited to the area of the injection. Moreover, transplanted cells undergo a rapid and massive death (80%) soon after the injection, though this can be prevented by immunosuppressive therapy.23 The need for direct injection of a large number of cells at high density in all muscles of the body makes this approach impractical. The recent identification of subpopulations of stem cell which can reach skeletal muscle with arterial injection has boosted new hopes in the cellular approach. Stem cells have the ability of self renewal and give rise to progenitor or precursor cells before differentiating into other cells. A promising study on the mdx mouse has shown that human-derived ­ pericytes, usually embedded in the basal membrane of microvessels, can differentiate into satellite stem cells.24 These studies have been paralleled by the identification of similar cells in the GRMD and their transplantation resulted in some functional success.25 Clinical trials using pericytes are now being planned in DMD.

Disclosures Two of the authors (FM and MK) are involved in a phase I/II trial using morpholino antisense oligomers in DMD. The study is funded by the Department of Health, and Imperial College ­London is the study sponsor. ◆

Read-through of stop codon mutations This technique is applicable to ∼7–10% of patients with DMD who have nonsense mutations in the dystrophin gene. Aminoglycosides can cause misreading of the RNA code, allowing insertion of alternative amino acids at the site of the mutated codon, transcription and protein formation.26 This was originally shown with gentamycin in the mdx mouse,26 although the results were not replicated in human trials. More recently, PTC-124, a novel orally administered molecule with a similar mechanism of action as gentamycin, has been shown to be more efficient and less toxic in two human clinical trials on healthy volunteers.27 A phase II clinical trial in DMD is underway and preliminary manufacturer’s data (October 2006) suggest that it is safe and well tolerated.

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References 1 Muntoni F, Torelli S, Ferlini A. Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2003; 2: 731–740. 2 Eagle M. Report on the muscular dystrophy campaign workshop: exercise in neuromuscular diseases Newcastle, January 2002. Neuromuscul Disord 2002; 12: 975–983.

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3 Rodillo EB, Fernandez-Bermejo E, Heckmatt JZ, et al. Prevention of rapidly progressive scoliosis in Duchenne muscular dystrophy by prolongation of walking with orthoses. J Child Neurol 1988; 3: 269–274. 4 Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2004(2): CD003725. 5 Bushby K, Muntoni F, Urtizberea A, et al. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2–4 April 2004, Naarden, The Netherlands. Neuromuscul Disord 2004; 14: 526–534. 6 Quinlivan R, Roper H, Davie M, et al. Report of a Muscular Dystrophy Campaign funded workshop Birmingham, UK, January 16th 2004. Osteoporosis in Duchenne muscular dystrophy; its prevalence, treatment and prevention. Neuromuscul Disord 2005; 15: 72–79. 7 Escolar DM, Buyse G, Henricson E, et al. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Ann Neurol 2005; 58: 151–155. 8 Fowler EG, Graves MC, Wetzel GT, et al. Pilot trial of albuterol in Duchenne and Becker muscular dystrophy. Neurology 2004; 62: 1006–1008. 9 Simonds AK. Recent advances in respiratory care for neuromuscular disease. Chest 2006; 130: 1879–1886. 10 Ward S, Chatwin M, Heather S, et al. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005; 60: 1019–1024. 11 Duboc D, Meune C, Lerebours G, et al. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005; 45: 855–857. 12 Bourke JP. Cardiac monitoring and treatment for children and adolescents with neuromuscular disorders. Dev Med Child Neurol 2006; 48: 164. 13 Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13: 166–172. 14 Kinali M, Main M, Eliahoo J, et al. Predictive factors for the development of scoliosis in Duchenne muscular dystrophy. Eur J Paediatr Neurol 2007; 11: 160–166. 15 Muntoni F, Bushby K, Manzur AY. Muscular Dystrophy Campaign Funded Workshop on Management of Scoliosis in Duchenne Muscular Dystrophy 24 January 2005, London, UK. Neuromuscul Disord 2006; 16: 210–219. 16 Pane M, Vasta I, Messina S, et al. Feeding problems and weight gain in Duchenne muscular dystrophy. Eur J Paediatr Neurol 2006; 10: 231–236. 17 Eagle M, Bourke J, Bullock R, et al. Managing Duchenne muscular dystrophy – the additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscul Disord 2007; 17: 470–475. 18 Parker AE, Robb SA, Chambers J, et al. Analysis of an adult Duchenne muscular dystrophy population. QJM 2005; 98: 729–736. 19 Friedman KJ, Kole J, Cohn JA, et al. Correction of aberrant splicing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by antisense oligonucleotides. J Biol Chem 1999; 274: 36193–36199. 20 Gregorevic P, Allen JM, Minami E, et al. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 2006; 12: 787–789.

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21 Wang Z, Kuhr CS, Allen JM, et al. Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol Ther 2007; 15: 1160–1166. 22 Tinsley JM, Davies KE. Utrophin: a potential replacement for dystrophin? Neuromuscul Disord 1993; 3: 537–539. 23 Skuk D, Goulet M, Roy B, et al. First test of a “high-density injection” protocol for myogenic cell transplantation throughout large volumes of muscles in a Duchenne muscular dystrophy patient: eighteen months follow-up. Neuromuscul Disord 2007; 17: 38–46. 24 Dellavalle A, Sampaolesi M, Tonlorenzi R, et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 2007; 9: 255–267. 25 Sampaolesi M, Blot S, D’Antona G, et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 2006; 444: 574–579. 26 Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 1999; 104: 375–381. 27 Hirawat S, Welch EM, Elfring GL, et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007; 47: 430–444. 28 Wells DJ. Therapeutic restoration of dystrophin expression in Duchenne muscular dystrophy. J Muscle Res Cell Motil 2006; 27: 387–398. 29 Alter J, Lou F, Rabinowitz A, et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 2006; 12: 175–177.

Practice points • Multidisciplinary team input with follow-up in specialized centres is the key to optimal management • Regular physiotherapy by parents and use of night ankle splints in the ambulant stages prevents/controls lower limbs contractures • Rehabilitation in knee–ankle–foot orthoses (KAFOs) is effective in prolonging walking for an average of 2 years • Glucocorticoid corticosteroids should be offered to all ambulant patients from the age of 4 years onwards • Close monitoring for corticosteroid dose adjustment, based on response and adverse effects, is essential • Regular echocardiographic monitoring (every 2 years until age 10 and then annually) allows early treatment of cardiomyopathy • Scoliosis management is individualized, depending upon age, rate of scoliosis progression and cardiorespiratory function • Annual sleep studies, once FVC is ≤ 60%, and surveillance for symptoms of sleep hypoventilation, allow timely introduction of non-invasive ventilatory support • Night-time non-invasive ventilation is well tolerated, relieves symptoms and improves survival • Every unit should develop robust protocols for transition of care to adult medical teams

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Symposium: neurology

Management of neonatal hydrocephalus

arises in choosing the best treatment option for a ­particular aeti-­ ology and is discussed below. Intraventricular haemorrhage Full term IVH probably occurs more often than we think but is more common at lower birth weights.3–5 IVH does not invariably cause HC. There is controversy as to how HC follows IVH. Some have suggested that proteinaceous material blocks the arach-­ noid granulations, thus resulting in excess cerebrospinal fluid (CSF) due to reduced reabsorption.6 In some cases there must be some kind of block to CSF passage at the exit foraminae of the fourth ventricle, as this would explain why endoscopic third ventriculostomy (ETV) works in some patients with IVH (18%).7 However, the majority need to have shunts inserted and, despite many recently advocating the use of ETV,8–11 this is still consid-­ ered by most to be the treatment of first option. ETV has also been used to washout heavy protein loaded CSF and to enable shunting to be implemented somewhat earlier or even avoided.12 In heavy blood/protein loaded CSF, drainage may be needed for some time before shunting to reduce the risk of shunt blockage, although lumbar drainage has been successful in avoiding shunting in IVH (see below).13

Neil Buxton

Abstract Neonatal hydrocephalus is a complex disorder due to many different causes. This review seeks to encapsulate the management of neonatal hydrocephalus in the term neonate. The current treatments are explored and explained.

Keywords hydrocephalus; intraventricular haemorrhage; neonatal ­meningitis; neonates; shunts

Neonatal meningitis Meningitis can also lead to HC. This may be due to a heavy pro-­ tein load causing problems at the arachnoid granulations or dis-­ crete blockages of exit foraminae by debris or membranes. Hence, again, ETV has been shown to be effective in some post-­meningitic HC cases but the majority will require shunt insertion. During the acute, infective phase, and whilst there is heavy protein load in the CSF, it may be necessary to drain the HC with an external ventricular drain (EVD) in order to reduce the intra-­ cranial hypertension. Obviously, such a device can be used to drain excess CSF, but is also useful for obtaining CSF samples for serial cultures and for the administration of intraventricular anti-­ biotics (a technique restricted to specialist neurosurgical units). Draining the CSF in this way will allow it to return to its normal constituent levels, so allowing shunting to be implemented. It is generally believed that the higher the protein load of the CSF the more likely it is that the shunt will fail due to blockage by debris; this is not the case with HC secondary to tuberculous meningitis. In these circumstances, the protein load is much less important and shunting can take place earlier.14,15

Introduction Neonatal hydrocephalus (NHC) is increasingly becoming the most difficult management problem in paediatric neurosurgery but survival from the hydrocephalus has improved.1 There are many problems associated with aetiology, body weight and immaturity, including unfused sutures, relating to risks of infec-­ tion and controversies with actual treatment protocols. This review is intended to give an overview of current thoughts on the management of hydrocephalus in the term neonate. The manage-­ ment of hydrocephalus (HC) in the premature child will not be covered. Neonatal hydrocephalus occurs in approximately 1 in 1000 live births. It is secondary to full term intraventricular haem-­ orrhage (IVH), infection or congenital causes such as tumours, aqueduct stenosis, Dandy–Walker syndrome and its variants or, of course, it can be truly idiopathic. Where possible, treatment of the cause is the first priority but in many cases the treatment of the hydrocephalus takes prece-­ dence. For example, in meningitis with HC, draining an enlarged ventricular system may be necessary even before the infection has been completely cleared. Birth weight influences treatment choices as well. There is a reluctance to introduce any permanent shunt systems into a child less than 2 kg in weight because below this weight there is a substantially increased risk of shunt failure due to infection.2 Fortunately, most term babies exceed this weight.

Non-communicating hydrocephalus The terminology communicating and non-communicating hydro-­ cephalus is becoming controversial, partly because of issues with post-infectious and post-haemorrhagic HC, as briefly men-­ tioned above. It is clear that tumours, aqueduct stenosis and Dandy–Walker syndrome and its variants can have physical blocks to the passage of the CSF, and thus can lead to truly non­communicating HC. In these types of HC, seemingly in all ages, ETV is the treatment of choice.16,17 Unfortunately, ETV in the truly non-communicating hydro-­ cephalus in some younger children will still fail. There are no accepted theories for this but it may be that the pressure of CSF required to initiate CSF reabsorption via the arachnoid granu-­ lations exceeds the pressure needed to expand the cranium in those with unfused sutures; in such a situation, ETV is certain to

Treatment choices All authorities in Western countries agree that, except in the most devastating of circumstances, the HC should be treated. ­Difficulty

Neil Buxton MB ChB DMCC FRCS(Ed) FRCS(Neuro Surg) is a Consultant Paediatric Neurosurgeon, Royal Liverpool Children’s Hospital, Liverpool, UK.

PAEDIATRICS AND CHILD HEALTH 18:1

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Symposium: neurology

fail and a shunt is required. Whilst seemingly very simple, shunt-­ ing is controversial too and in order to address this small number of children and their requirements an international randomized trial is looking at the efficacy of shunting versus ETV.

c­ ommon alternatives include the right atrium via a neck vein and the superior vena cava (the historical site of choice) and also the pleural space. The pleura is used as a last resort in those in whom there has been extensive abdominal surgery, peritonitis or necrotizing enterocolitis, and whose neck veins have been dam-­ aged by central lines. Pleural shunts always cause effusions and, if there is a significant CSF volume, then the effusion resulting may embarrass lung function. A balance must be struck. Simi-­ larly, in the abdomen there can be a bulging tense abdominal wall and the development of CSF hydrocoeles.

Idiopathic So-called idiopathic HC is best treated by treating the underlying anatomical precedence. If there is evidence of flow obstruction, then ETV may well work; otherwise it is likely that shunting will be required. Tumours In the presence of third or fourth ventricular tumours or tectal plate or brainstem tumours causing HC, the HC can easily be treated by ETV and in some biopsies obtained.11,18 In successful resection of a cerebellar tumour, for example, CSF flow may be restored and no longer requires diversion. ETV or shunt is often needed, however, although temporary EVD may ‘buy enough time’ for definitive tumour treatment. Arachnoid cysts in or near the third ventricle behave like tumours and can be successfully managed by ETV.19

Shunt failure This is almost inevitable in the lifetime of a patient with a shunt, with the greatest number, approximately 20%, occurring in the first year after insertion. Failure manifests itself in many ways, e.g. increased head circumference, tense fontanel, drowsiness, vomit-­ ing, squint, CSF tracking alongside the shunt tubing, signs of infec-­ tion, and banging the head with the hands or against something, which can indicate headache. In these circumstances shunt revi-­ sion is usually required. It is a neurosurgical rule that if the primary carer says that the child is ‘not right’ and that they ‘think it’s the shunt’, it is a brave and foolhardy person to ignore the warning. In some in whom a shunt subsequently fails, an ETV may well work and paediatric neurosurgeons will always assess a ‘new’ shunt failure for anatomical suitability for the procedure.9,22,23

Low birth weight If the birth weight is less than 2 kg, then shunting tends not to be ­recommended.2 This is because of concerns about the anaesthetic, neonatal care, risk of infection, operating on someone so small, etc, with infection of the shunt being the most worrisome. The HC can be ameliorated until the baby gains weight by serial lumbar punctures, serial ventricular taps, an EVD (which can be used up to 3 weeks without changing, with care) or a more permanent Ommaya reservoir (an implanted ventricular tube with an injection part).20 Intuitively there is concern about introducing a permanent or semi-permanent foreign body into the child, just as there is con-­ cern definitive shunting; however, this seems to be safe in cases of low birth weight and post-haemorrhagic hydrocephalus.21

Conclusion The numbers of children surviving to term in the West with HC are increasing as better obstetric care, earlier antenatal diagnosis and better awareness lead to more informed decisions. In the last 20 years, paediatric neurosurgery has evolved into a distinct subspecialty on a par, for example, with spinal neurosurgery. More aggressive, better targeted treatment for paediatric HC, no longer in isolation from other children’s specialists, provided by surgeons with expertise and training in the management of these difficult clinical scenarios is improving the situation for these patients. Treatment in the West has moved out of the hands of paediatric general surgeons but their historical contribution can-­ not be underestimated as without their skills and expertise there would be no paediatric neurosurgery at all. With the develop-­ ment of paediatric neurosurgical centres there is no longer an excuse to dabble in the management of such complex problems and such an approach is to be discouraged. ◆

Which shunt? The type of shunt largely depends on the individual surgeon, their experience with a particular model and their own biases. Whilst this approach is not scientifically sound, a surgeon will get ‘used’ to a particular model, understand its idiosyncrasies and become confident with its use. This is perhaps more impor-­ tant than any other consideration such as cost, ‘newness’, etc, as the surgeon uses their own experience to decide what is best for a particular patient. This is where experience counts and, dare it be said, some of the art in the science remains. Notwithstanding all of the above, most would agree that the smaller the child the less bulky the shunt and the quicker it should be to insert, with fewer components to increase surgery time (hence infection risk) and in the long run with fewer options for malfunction. Unfor-­ tunately, the answer to the problem of deranged physiology is difficult to identify when we have mechanical devices with fixed tolerances for, literally, a fluid system. Where does the distal end go? Obviously in treating HC we are inserting the upper end into the lateral ventricle. This tends to be on the right (the non-dominant hemisphere). This is con-­ nected to a one-way valve device to the distal catheter. The dis-­ tal end is placed into the peritoneal cavity by choice, although

PAEDIATRICS AND CHILD HEALTH 18:1

References 1 Chi JH, Fullerton HJ, Gupta N. Time trends and demographics of deaths from congenital hydrocephalus in children in the United States: National Center for Health Statistics data, 1979 to 1998. J Neurosurg 2005; 103(suppl 2): 113–118. 2 Bruinsma N, Stobberingh EE, Herpers MJ, et al. Subcutaneous ventricular catheter reservoir and ventriculoperitoneal drain related infections in preterm infants and young children. Clin Microbiol Infect 2000; 6: 202–206. 3 Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birth weight infants. Am J Obstet Gynecol 2007; 196: 147 e1–8.

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4 Fink S. Intraventricular haemorrhage in the term infant. Neonatal Netw 2000; 19: 13–18. 5 Prat Puig M, Campistol Plana J, Muniz Llama F, et al. Intraventricular haemorrhage in healthy newborn infants at term. An Esp Pediatr 1987; 27: 107–111. 6 Cherian S, Whitelaw A, Thoresen M, et al. The pathogenesis of neonatal posthemorrhagic hydrocephalus. Brain Pathol 2004; 14: 305–311. 7 O’Brien DF, Seghedoni A, Collins DR, et al. Is there an indication for ETV in young infants in aetiologies other than isolated aqueduct stenosis? Childs Nerv Syst 2006; 22: 1565–1572. 8 Scavarda D, Bednarak N, Litre F, et al. Acquired aqueductal stenosis in preterm infants: an indication for neuroendoscopic third ventriculostomy. Childs Nerv Syst 2003; 19: 756–759. 9 Giomin V, Cinalli G, Grotenhuis A, et al. Endoscopic third ventriculostomy in patients with CSF infection and/or hemorrhage. J Neurosurg 2002; 97: 519–524. 10 Scarrow AM, Levy EI, Pascucci L, et al. Outcome analysis of endoscopic third ventriculostomy. Childs Nerv Syst 2000; 16: 442–444. 11 Macarthur DC, Buxton N, Punt J, et al. The role of neuroendoscopy in the management of brain tumours. Br J Neurosurg 2002; 16: 465–470. 12 Kamikawa S, Inui A, Kobayashi N, et al. Intraventricular hemorrhage in neonates: endoscopic findings and treatment by the use of our newly developed Yamadori type 8 ventriculoscope. Minim Invasive Neurosurg 2001; 44: 74–78. 13 Huttner HB, Schwab B, Bardutzky J. Lumbar drainage for communicating hydrocephalus after ICH with ventricular haemorrhage. Neurocrit Care 2006; 5: 193–196. 14 Kemaloglu S, Ozkan U, Bukte M, et al. Timing of shunt surgery in childhood tuberculous meningitis with hydrocephalus. Pediatr Neurosurg 2002; 37: 194–198. 15 Palur R, Rajshekhar V, Chandy MJU, et al. Shunt surgery for hydrocephalus in tuberculous meningitis: a long term follow-up study. J Neurosurg 1991; 74: 64–69.

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16 Baldauf J, Oertal J, Gaab MR, et al. Endoscopic third ventriculostomy in children younger than 2 years of age. Child Nerv Syst 2007; 23: 623–626. 17 Koch D, Wagner W. Endoscopic third ventriculostomy in infants less than 1 year of age: which factors influence the outcome? Child Nerv Syst 2004; 20: 405–411. 18 Javadpour M, Mallucci CL. The role of neuroendoscopy in the management of tectal gliomas. Childs Nerv Syst 2004; 20: 852–857. 19 Kirollos RW, Javadpour M, May P, et al. Endoscopic treatment of suprasellar and third ventricle related arachnoid cysts. Child Nerv Syst 2001; 17: 713–718. 20 Khalil BA, Sarsam Z, Buxton N. External ventricular drains: Is there a time limit in children? Childs Nerv Syst 2005; 21: 355–357. 21 Peretta P, Ragazzi P, Carlino CF, et al. The role of Ommaya reservoir and endoscopic third ventriculostomy in the management of posthaemorrhagic hydrocephalus of prematurity. Child Nerv Syst 2007; 23: 765–771. 22 O’Brien DF, Javadpour M, Collins DR, et al. Endoscopic third ventriculostomy: An outcome analysis of primary cases and procedures performed after ventriculoperitoneal shunt malfunction. J Neurosurg 2005; 103(suppl 5): 393–400. 23 Buxton N, Macarthur D, Robertson I, et al. Neuroendoscopic third ventriculostomy for failed shunts. Surg Neurol 2003; 60: 201–203.

Practice points • Neonatal hydrocephalus has varied aetiology • Choice of method of treatment for the hydrocephalus can depend heavily on the aetiology • Early consultation with a paediatric neurosurgeon is essential

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Symposium: neurology

Tuberous sclerosis complex

the genetics and the mechanism of the disease, such that potential new therapeutic avenues are opening.

Finbar O’Callaghan

Epidemiology By the standards of many genetic diseases, TSC is common. The best epidemiological studies suggest it has a prevalence in the region of 4–5 per 100 000 of the population. It affects all ethnic groups and is found equally commonly in both sexes.3

Genetics Abstract

TSC is inherited in an autosomal dominant fashion, i.e. if an individual has the disease, they have a 1 in 2 chance of passing the disease on to each of their offspring. However, approximately 70% of cases of TSC will be new mutations, such that neither the child’s father nor mother is affected with the disease. Occasionally, apparently unaffected parents may have more than one affected child and this may be because of the phenomenon of gonadal mosaicism, i.e. the situation where an apparently unaffected parent has a population of affected cells confined to their gonads and who is therefore liable to have more than one affected child (Figure 1).4,5 Linkage studies in multigenerational families demonstrated that two genes were responsible for TSC: one gene (TSC1) on chromosome 9 and one on chromosome 16 (TSC2).6–9 Mutations in either gene can cause all the clinical manifestations of TSC, although TSC1 appears to be associated with a slightly milder clinical phenotype.10 The frequency of mutations described is considerably higher in TSC2 than in TSC1.11 This disparity may be because there is an ascertainment bias in that TSC2 is ­associated with more severe disease or it may reflect an increased level of germline or somatic mutations in TSC2.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in multiple ­organs. It is caused by mutations in either the TSC1 gene on ­chromosome 9 or the TSC2 gene on chromosome 16. Both genes are tumour ­suppressor genes and the protein products of the two genes, hamartin and tuberin, co-localize in the cell and help regulate cell growth by inhibiting the mammalian target of rapamycin (mTOR) in the akt-mTOR-S6 kinase cell growth pathway. The discovery of the TSC proteins’ role in this intracellular pathway has recently lead to investigation of chemotherapeutic agents, such as rapamycin (sirolimus), that also influence this pathway and that may partly substitute for their role in regulating cell growth. Clinically, the disease commonly causes epilepsy, learning difficulties and behavioural problems (autism, hyperactivity and sleep disturbance), although as many as half of affected individuals may have a normal IQ. Life-threatening hamartomas may develop during life in the kidneys (renal angiomyolipomas) and brain (subependymal giant cell astrocytomas). Clinicians need to watch carefully for these complications. Patients with TSC will require multidisciplinary clinical involvement and, preferably, this should be coordinated through a ­specialist TSC clinic.

Keywords angiomyolipoma; epilepsy; giant cell astrocytoma; ­ mTOR; tuberous sclerosis

Introduction Clinicians have been aware of tuberous sclerosis complex (TSC) as a distinct clinical entity for approximately 125 years since Desiree Magloire Bourneville described the first case in 1880. For most of that time they believed that the disease inevitably led to severe learning difficulties and intractable epilepsy, but since the clinical and epidemiological work in the late 20th century they now realize that the disease manifests in virtually every organ and that often, perhaps in the majority cases, it may be associated with normal intelligence levels.1,2 The disease is characterized by the formation of hamartomas in multiple organs. In the last 20 years major advances have been made in our ­understanding of

Finbar O’Callaghan MA MB ChB MSc PhD FRCPCH is a Consultant Senior Lecturer in Paediatric Neurology, Institute of Child Life & Health, Department of Clinical Sciences @ South Bristol, University of Bristol, Bristol, UK.

PAEDIATRICS AND CHILD HEALTH 18:1

Figure 1 The concept of gonadal mosaicism i.e. where an apparently unaffected parent can have more than one affected child because they have a population of affected cells within their gonads.

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Symposium: neurology

We are now able to look for mutations in TSC1 and TSC2 in apparently affected individuals. However, even in the best ­laboratories, mutations are only being described in ­approximately 80% of cases. This may be because of somatic mosaicism whereby an affected individual has two populations of cells: one population has a mutation in one of the TSC genes and one does not have a mutation in the TSC genes.12 The fact that we can now screen for mutations in TSC1 and TSC2 raises the possibility of antenatal screening for TSC but it should be remembered that the phenomenon of somatic mosaicism means that a negative result on chorionic villous sampling does not completely exclude the possibility that a fetus may develop the disease. It is thought that TSC1 and TSC2 are tumour suppressor genes, i.e. that their function is to help regulate cell growth and differentiation. When altered, by mutation, control of cell growth is disturbed and tumours form throughout the body. Some of the strongest evidence supporting the idea that the TSC genes are tumour suppressor genes has been the demonstration that some of the hamartomas in tuberous sclerosis patients show loss of heterozygosity (LOH) either in the chromosomal region 9q34 or in 16p13.13,14 The loss of heterozygosity implies that an individual with tuberous sclerosis inherits or acquires through mutation a deletion in one copy of the gene but only develops a lesion when there is a somatic mutation in the other copy. These second mutations are usually large and involve the loss of surrounding loci. This two-hit mechanism was first proposed by Knudson in the early 1970s to explain the pathogenesis of retinoblastoma. LOH has been demonstrated consistently in many TSC lesions such as cardiac rhabdomyomas, renal angiomyolipomas and subependymal giant cell tumours. The two-hit mechanism does not, however, appear to operate in all TSC lesions. LOH is rarely demonstrated in cerebral tubers. It has been suggested that haploinsufficiency is sufficient to lead to the development of cerebral tubers even in the presence of a ‘normal’ copy of the TSC gene on the second allele.

and proliferation (Figure 2). The hamartin–tuberin complex acts through a molecule called Rheb (RAS-homologue expressed in brain) to inhibit the mammalian target of rapamycin (mTOR) which, without this inhibition, activates S6 kinase and therefore cell growth and proliferation.18,19 Rapamycin and inhibition of mTOR There has recently been much interest in the possibility of using a drug called rapamycin (sirolimus) in patients with TSC. Rapamycin is a licensed drug that has been used for some time as an immunosuppressant in transplant patients. It is also an inhibitor of mTOR and therefore would theoretically inhibit the activity of S6 kinase in patients with TSC in whom the hamartin–tuberin complex is not working effectively. There is clear proof that rapamycin has a biological effect in TSC patients. It has been shown, for instance, to cause regression in the size of subependymal giant cell astrocytomas.20 However, there are still problems with its use in TSC patients. Rapamycin is a relatively toxic drug and

Disease mechanism at the molecular level The protein products of the TSC1 and TSC2 genes are named hamartin and tuberin, respectively. Hamartin is a 140 kDa, 1164 amino acid protein that is expressed in most adult tissues. It has a coiled-coil domain. It probably has a role in regulating cell adhesion. Hamartin interacts with the Ezrin–Radixin–Moiesin family of actin-binding proteins. Inhibition of hamartin function in cells results in loss of cell substrate adhesion and it has been suggested that this may have a role in initiating the development of TSC hamartomas. Tuberin is a 200 kDa, 1807 amino acid protein with a region near the carboxy terminal that is homologous with GTPase activating protein (GAP). The GAP activity of TSC2 is thought to be essential for its physiological function.15–17 Substantial progress in our understanding of the molecular function of tuberin and hamartin has come from experiments in the fruit fly, drosophila. It was found that mutations in the drosophila homologues of the TSC1 and TSC2 genes resulted in increased cell and organ size.18 It has been known for some time that hamartin and tuberin co-localize in the cell.15,16 It has recently been discovered that they act together in the P13 kinaseakt-S6 kinase pathway. This pathway is stimulated by insulin and insulin-like growth factors, and it helps to regulate cell growth

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Figure 2 A schematic diagram of the P13 kinase – Akt – S6 kinase pathway. TSC1-TSC2 inhibit the activity of mTOR via the molecule Rheb. Rapamycin, a commercially available drug, also inhibits mTOR. The net affect of both TSC1-TSC2 complex and rapamycin is to inhibit S6 kinase and thereby help regulate cell growth.

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is known to cause apthous ulceration, interstitial pneumonitis and hyperlipidaemia. Its therapeutic effects in TSC patients may only last for as long as a patient is undergoing treatment, i.e. when treatment stops the hamartomas may re-grow. If life-long treatment with a relatively toxic drug is going to be necessary to maintain a therapeutic benefit, then many patients may opt for other treatment options, e.g. surgery. Much work still needs to be done to investigate the role of mTOR inhibitors in TSC and, currently, they should not be used outside the context of a ­clinical trial.

Clinical manifestations Brain Three lesions can arise in the brain in individuals with TSC: tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGA). Tubers are the lesions that give the disease its name (Figure 3). They are developmental abnormalities of the cerebral cortex. The lesions have lost the normal six-layered laminar architecture of the cerebral cortex and contain ­ dysplastic neurones, astrocytes and characteristic giant cells (Figure 4). Tubers can be identified in fetal life and persist throughout life. It is thought that tubers do not increase in number after birth, although they may become more visible on magnetic resonance imaging (MRI) as the brain myelinates in the first 2–3 years of life. The tubers are thought to underlie the epilepsy that occurs in approximately 75% of TSC individuals. Epilepsy may begin in the first year of life with infantile spasms. These epileptic spasms are probably most effectively treated with the GABA inhibitor, vigabatrin.21 In later life, individuals with TSC may develop multiple different types of seizures (e.g. focal seizures, atonic seizures, atypical absences) that are often refractory to anticonvulsant medication. Some individuals will develop the

Figure 4 Histological slide of a tuber showing characteristic giant cel (arrowed).

epileptic encephalopathy, Lennox–Gastaut syndrome. Sometimes it is possible to identify the ‘epileptogenic tuber or tubers’ and in these patients epilepsy surgery should be considered early in order to prevent the damage that can result from epileptic ­encephalopathies such as West syndrome or Lennox–Gastaut syndrome. A recent meta-analysis of epilepsy surgery in TSC has shown that 57% of patients achieve seizure freedom following surgery.22 Subependymal nodules are small hamartomas that are found on the walls of the lateral ventricles. They are usually multiple and are sometimes calcified. There is no evidence that, per se, they cause any neurological symptoms. They are the second most common cerebral feature of TSC. The nodules are easily visualized by computerized tomography (CT) but they may also be seen on MRI. Subependymal giant cell astrocytomas (SEGAs) occur in approximately 5% of patients with TSC (Figure 5). It is possible that they arise from pre-existing subependymal nodules but

Figure 3 Magnetic Resonance Image (axial cut, FLAIR sequence) showing multiple cerebral tubers in Tuberous Sclerosis Complex patient.

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Figure 5 CT scan of brain of an individual with TSC who has a subependymal giant cell astrocytoma at the foramen of Monro (arrowed).

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­transitory but significant pain and fever and this can be controlled with analgesia and steroids.29 Cysts are the second most common renal manifestation of TSC. They arise from anywhere within the nephron. Occasionally, the mass effect from cysts can compromise renal function. Cysts can be associated with either TSC1 or TSC2 disease. Rarely, a particularly severe phenotype occurs when there is a contiguous deletion of the TSC2 gene and the polycystic kidney disease gene (PKD1) on chromosome 16. In these patients, polycystic kidneys develop in early childhood and usually result in renal failure in adolescence or early ­adulthood.30

this has not been conclusively proven. They are histologically indistinguishable from subependymal nodules. They arise most often in the region of the foramen of Monro and cause clinical problems by blocking the flow of cerebrospinal fluid in the ventricular system. Untreated they can cause raised intracranial pressure leading to hydrocephalus, blindness and, even, death. Clinicians should be vigilant for signs and symptoms of raised intracranial pressure and symptomatic lesions should be surgically removed. Cognition and psychopathology: there is a bi-modal distribution of intelligence in individuals with TSC. There is a population of individuals with severe learning difficulties and a population with a normal distribution of IQ around a mean of approximately 90. More than half of individuals with TSC will have an IQ that will fall within the range of normal for the ­general population (i.e. greater than 70). Both the infantile encephalopathy and the number of cerebral tubers are thought to influence the level of intelligence in the TSC population, although, in an individual case, it should be remembered that normal intelligence can be achieved even in the presence of many tubers and a history of infantile spasms.23 Autism and hyperactivity are also common in TSC. Again, the autism may be related to tuber number and location. Tubers in the temporal lobe may be associated with an increased risk of autism. Psychopathologies, such as depression and anxiety, have also been found to be more common in TSC individuals than unaffected controls.3,24,25

Pulmonary lesions An interstitial lung disease, known as lymphangioleiomyomatosis (LAM), occurs in female TSC patients. It affects somewhere between 26% and 39% of women with TSC. The onset is usually in adolescence or adulthood. The disease is characterized by the proliferation of abnormal smooth muscle cells and cystic changes within the parenchyma of the lung. Clinical symptoms are dyspnoea and pneumothorax. It is best diagnosed using high-resolution CT of the chest. There is no recognised effective treatment that reverses the progression of the lung disease and it is one of the causes of early mortality in TSC patients.31 Concept of ‘benign metastases’: it has been found that women who do not have germline mutations in their TSC1 or TSC2 genes can develop both lymphangioleiomyomatosis and renal angiomyolipomas. In these patients, identical TSC2 mutations have been identified in cells from their abnormal renal and ­pulmonary lesions that are not identifiable anywhere else (i.e. in DNA from blood). This finding suggests that these women have developed lung and kidney lesions from a single progenitor cell. Consequently, investigators have developed a ‘benign metastasis’ model that proposes that histologically ‘benign metastases’ (i.e. not cancerous) with mutations in TSC1 or TSC2 travel from renal angiomyolipomas to the lung (Figure 6). It is postulated that cells with TSC1 or TSC2 mutations have decreased cell adhesion and therefore an increased motility. It is not understood why this phenomenon occurs almost exclusively in women, although it is suggested that oestrogen, in some way, must alter TSC signalling.32

Cardiac lesions Cardiac rhabdomyomas are the commonest cardiac tumours of childhood and they are often associated with TSC. They can be detected on antenatal ultrasound scanning. They occur within any of the four heart chambers as intracavity or intramural tumours but they are most commonly seen in the left ventricle. Clinically they can cause problems in the postnatal period because they obstruct ventricular function and outflow, and they may need to be removed surgically. They can also cause rhythm disturbances when the rhabdomyomatous tissue acts as an accessory conducting pathway predisposing the patient to pre-excitation syndromes such as Wolff–Parkinson–White syndrome. The rhabdomyomas regress in size after birth and although they may still be visible on echocardiograms, they rarely cause problems outside the postnatal period.26–28

Skin lesions There are multiple skin lesions associated with TSC. None of the lesions causes a significant clinical problem although because they can sometimes be disfiguring there may be considerable psychological distress. The cutaneous lesions characteristically appear at different ages. Hypomelanic macules or ‘ash-leaf patches’ are areas of white skin that can most easily be visualized by an ultraviolet (Wood’s) light. They are often present at birth or in early infancy. Facial angiofibromatosis, a red maculopapular rash, develops later in childhood and continues to progress through adolescence and adulthood. This lesion can be significantly disfiguring and may require laser treatment for cosmetic reasons. The ‘shagreen patch’ is an area of raised roughened skin that characteristically appears in the small of the back but can occur anywhere on the trunk. It tends to appear in childhood. Ungual fibromas are small lesions that appear around the

Renal lesions Renal angiomyolipomas, hamartomas comprised of smooth muscle, fat and abnormal blood vessels, occur in up to 75% of patients with TSC. They do not usually appear before the age of 5. In most patients they will remain asymptomatic but in a small proportion they will cause clinical problems secondary to haemorrhage. The lesions are easily visualized by ultrasound scanning when they are visible as bright hyperechoic lesions. Patients with large angiomyolipomas (i.e. greater than 3.5–4 cm in diameter) are at the greatest risk of suffering from haemorrhage. Bleeding angiomyolipomas can be treated successfully with selective arterial embolization. This method of treatment can stop haemorrhaging whilst preserving the maximum amount of functioning renal tissue. Sometimes the process of ­embolization causes

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Tuberous sclerosis complex related lesions Facial angiofibromatosis or forehead fibrous plaque Periungual fibromas Shagreen patch Retinal astrocytoma Cortical or subcortical tuber Subependymal nodule Subependymal giant cell astrocytoma Renal angiomyolipoma or pulmonary lymphangioleiomyomatosis Cardiac rhabdomyoma The demonstration of two of these lesions in one individual constitutes clinical proof of a diagnosis of TSC. Note: Renal angiomyolipoma and pulmonary lymphangioleiomyomatosis count as one lesion for the purposes of diagnosis.

Table 1

the disease in an individual, a full clinical examination, including inspection with Wood’s light and fundoscopy, and cranial imaging should be undertaken. Renal imaging may be helpful although sometimes this can be difficult to interpret and may confuse the issue. Echocardiography is only useful in young children as ­cardiac rhabdomyomas regress after birth. White patches (ashleaf patches, hypomelanic macules) do not count as hamartomas but are suggestive of the diagnosis. Greater than five hypomelanic macules on an individual are very rarely seen outside of the context of TSC. Once a diagnosis has been made, baseline assessment with cranial imaging and renal ultrasound scanning should take place if not already been done as part of the diagnostic workup. An ECG should also be done to look for any evidence of cardiac arrhythmias as pre-excitation syndromes, ­ including Wolf–­Parkinson–White syndrome, may occur in TSC. A neuro­ psychological assessment at the time of diagnosis is also ­appropriate. The frequency and timing of follow-up examinations in TSC is controversial. Some clinicians advocate regular screening with cranial imaging and renal ultrasound scanning. Others argue that regular screening is not warranted as the natural history of TSC lesions is not understood and therefore there is no guide as to how often follow-up imaging should be undertaken nor when an asymptomatic lesion should be treated. These clinicians advocate close supervision of TSC patients and a low threshold for repeat scanning if there is any significant clinical change in the patient or the appearance of any worrying clinical symptom or sign. Currently the medical advisors of the Tuberous Sclerosis Association (www.tuberous-sclerosis.org.) take the latter view in their guidelines. The management of TSC patients is often complex, requiring the input of many disciplines, e.g. neurology, urology, ­psychiatry, nephrology, psychology, neurosurgery, genetics, dermatology, plastic surgery, ophthalmology, cardiology, radiology and respiratory medicine. Ideally, management should be coordinated through one of the specialist TSC clinics distributed throughout the UK in Bath, Leeds, London (St Georges and Great Ormond Street), Cambridge, Northern Ireland and Scotland.

Figure 6 Diagram illustrating the concept of “benign metastasis” in linking renal and lung pathology in TSC patients i.e. cells migrate from angiomyolipomas in the kidney that then cause lymphangioleiomyomatosis in the lung.

nail beds in late adolescence and adulthood. The fibromas often cause a longitudinal ridge to occur in the nail growing beneath them.33

Management Despite the advances in genetics and genetic diagnosis of TSC, it is still important to be able to make a secure clinical diagnosis. Genetic testing, even in the best centres, is still only approximately 80% sensitive. There have been various published clinical criteria on how to make the diagnosis of TSC. Essentially it is necessary to demonstrate the presence of TSC-related hamartomas in two separate organs. These hamartomas occur rarely in the general population and so the discovery of two or more independent hamartomas in an individual strongly supports a diagnosis of TSC (Table 1). Individuals with a single hamartoma may have developed this through the random occurrence of two somatic mutations in a cell in that organ but this scenario is unlikely to occur twice in different organs in the same individual without an inherited or early embryonic mutation. In practice, it is often easy to find two hamartomas in affected individuals. To exclude

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14 Henske EP, Scheithauer BW, Short MP, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 1996; 59: 400–406. 15 van Slegtenhorst M, Nellist M, Nagelkerken B, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998; 7: 1053–1057. 16 Nellist M, van Slegtenhorst MA, Goedbloed M, et al. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem 1999; 274: 35647–35652. 17 Maheshwar MM, Cheadle JP, Jones AC, et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet 1997; 6: 1991–1996. 18 Kwiatkowski DJ. Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol Ther 2003; 2: 471–476. 19 Tee AR, Fingar DC, Manning BD, et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A 2002; 99: 13571–13576. 20 Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006; 59: 490–498. 21 Hancock E, Osborne JP, Milner P. The treatment of West syndrome: a Cochrane review of the literature to December 2000. Brain Dev 2001; 23: 624–634. 22 Madhavan D, Schaffer S, Yankovsky A, et al. Surgical outcome in tuberous sclerosis complex: A multicenter survey. Epilepsia 2007; 48: 1625–1628. 23 O’Callaghan FJ, Harris T, Joinson C, et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004; 89: 530–533. 24 Harrison JE, O’Callaghan FJ, Hancock E, et al. Cognitive deficits in normally intelligent patients with tuberous sclerosis. Am J Med Genet 1999; 88: 642–646. 25 Raznahan A, Joinson C, O’Callaghan F, et al. Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis. J Intellect Disabil Res 2006; 50: 561–569. 26 Webb DW, Thomas RD, Osborne JP. Cardiac rhabdomyomas and their association with tuberous sclerosis. Arch Dis Child 1993; 68: 367–370. 27 Jozwiak S, Kotulska K, Kasprzyk-Obara J, et al. Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics 2006; 118: e1146–1151. 28 O’Callaghan FJ, Clarke AC, Joffe H, et al. Tuberous sclerosis complex and Wolff-Parkinson-White syndrome. Arch Dis Child 1998; 78: 159–162. 29 O’Callaghan FJ, Noakes MJ, Martyn CN, et al. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int 2004; 94: 853–857. 30 Brook-Carter PT, Peral B, Ward CJ, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease - a contiguous gene syndrome. Nat Genet 1994; 8: 328–332. 31 Hancock E, Osborne J. Lymphangioleiomyomatosis: a review of the literature. Respir Med 2002; 96: 1–6. 32 Juvet SC, McCormack FX, Kwiatkowski DJ, et al. Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans. Am J Respir Cell Mol Biol 2007; 36: 398–408. 33 Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol 1996; 135: 1–5.

Conclusion TSC is a significant and disabling genetic condition and relatively common in comparison to the vast majority of genetic diseases. It causes severe and sometimes life-threatening pathology in ­multiple organs but particularly within the central nervous system, renal and respiratory systems. In recent years major advances have been made in our understanding of the genetics and mechanism of the disease such that we now understand more clearly how the products of the two TSC genes help regulate normal cell growth and how, when they are not functioning properly, as in TSC, there is a tendency to form hamartomas throughout the body. There is still much that we do not understand. We do not understand why some lesions only occur in women and why lesions appear at different ages. We do not yet know how to manipulate the S6 kinase pathway for the clinical benefit of our patients. The next decade promises to be both exciting and productive as we search for answers to these and other questions. ◆

References 1 Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci 1991; 615: 125–127. 2 Webb DW, Fryer AE, Osborne JP. Morbidity associated with tuberous sclerosis: a population study. Dev Med Child Neurol 1996; 38: 146–155. 3 Joinson C, O’Callaghan FJ, Osborne JP, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med 2003; 33: 335–344. 4 Yates JR, van Bakel I, Sepp T, et al. Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis. Hum Mol Genet 1997; 6: 2265–2269. 5 Rose VM, Au KS, Pollom G, et al. Germ-line mosaicism in tuberous sclerosis: how common? Am J Hum Genet 1999; 64: 986–992. 6 Fryer AE, Chalmers A, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987; 1: 659–661. 7 Kandt RS, Haines JL, Smith M, et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet 1992; 2: 37–41. 8 van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–808. 9 Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–1315. 10 Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68: 64–80. 11 Jones AC, Daniells CE, Snell RG, et al. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet 1997; 6: 2155–2161. 12 Kwiatkowska J, Wigowska-Sowinska J, Napierala D, et al. Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N Engl J Med 1999; 340: 703–707. 13 Sepp T, Yates JR, Green AJ. Loss of heterozygosity in tuberous sclerosis hamartomas. J Med Genet 1996; 33: 962–964.

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Practice points

associated with them. Clinicians should have a low threshold for repeat neuro- or renal imaging if there is any significant clinical change in their patients • Epilepsy occurs in approximately 75% of patients and learning difficulties in approximately 50% • Epilepsy surgery may provide a possible cure for epilepsy in TSC • Behavioural problems such as autistic spectrum disorders, hyperactivity and sleep disturbance may be the most problematic aspect of the condition for many parents • Potential treatments that mimic the effects of TSC proteins on intracellular growth pathways of TSC are now being investigated in clinical trials • Care for TSC patients should preferably be coordinated through specialist TSC clinics

• Tuberous sclerosis complex is an autosomal dominant genetic disease caused by mutations in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16 • The protein products of the two genes, hamartin and tuberin, act together within cells to regulate cell growth • The disease is characterized clinically by a tendency to form hamartomas in multiple organs • The hamartomas appear in different organs at different stages of life • Life-threatening hamartomas can develop in the kidney and brain during life and clinicians looking after TSC patients need to be aware of their development and the complications

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Long-term effects of cannabis

tried illicit drugs at some time. Cannabis was the most frequently tried drug and its use was strongly associated with cigarette smoking; 7% of non-smokers had tried cannabis compared to 89% of young people who had smoked greater than 10 cigarettes in the previous week.2 These figures represent a significant number of young people who may present to health professionals incidentally or as a consequence of difficulties encountered through substance misuse. Awareness of the current evidence regarding the possible longterm adverse consequences of regular cannabis use, in terms of physical, mental and social effects on the young person, is important for the health professionals working with and attempting to understand young people. Another significant but (probably) small subgroup is the offspring of women who have used cannabis during pregnancy.

Anna Boyce Paul McArdle

Abstract Cannabis use is common in young people and the drug is widely perceived as being the least harmful of the numerous illicit substances available. There is reasonable evidence, however, that long-term use of cannabis is associated with adverse psychosocial outcomes, and ­accumulating evidence that cannabis use may have a causal association with onset of psychosis. The role of cannabis as a ‘gateway’ to use of other drugs such as heroin is considered. Other adverse associations with cannabis use include impairment in driving skills, of which a longterm consequence may be serious injury, and a possible association with subtle cognitive deficits in children exposed to cannabis prenatally.

Short-term effects of cannabis The main psychoactive component of the cannabis plant is a cannabinoid compound – Δ9- tetrahydrocannabinol (Δ9 THC), although there are over 60 cannabinoids present in the body of the plant and the resin produced by the female plant. Cannabis is bought as resin (‘hash’) or marijuana, and can be smoked with tobacco in a joint, burned and inhaled in a bong or ‘bucket’, or cooked in food and eaten. The concentration and rate of absorption varies with method of use. Smoking and inhaling cannabis leads to a rapid rise in blood concentration of Δ9 THC. Ingesting cannabis in food results in a much more gradual absorption with effects being noticeable over several hours. Varieties of cannabis plants such as skunkweed are said to have a higher Δ9 THC concentration than traditional varieties. Cannabis is fat soluble and accumulates in adipose tissue with an elimination half-life of 7 days.3 Regular use of cannabis therefore leads to persistently high blood concentrations of Δ9 THC. Cannabis is thought to exert its central effects via the CNR1 cannabinoid receptor in the brain. These effects include euphoric and relaxed mood, a sense of detached observation and increased appetite, although anxiety symptoms may also be experienced. Cannabis intoxication causes impairments in concentration, fine motor skills and reaction times.4 Peripheral effects include conjunctival hyperaemia (‘red eye’), raised heart rate and alterations in blood pressure. Cannabis use or intoxication may have significant long-term consequences in terms of increased likelihood of injury following road traffic accidents. For instance, Mura et al5 compared the cannabis intake of 900 injured drivers with that of 900 matched controls presenting to the same hospitals and found that 10% of injured drivers had THC present in blood samples, with an odds ratio of 2.0, drivers to controls, increasing to an odds ratio of 2.5 in those under 27 years old. By comparison 26% of the injured drivers were over the legal limit for blood alcohol levels and the odds ratio was 3.8. A detailed review of the effects of cannabis use on driving ability can be found in Kalant.6 Tolerance to the effects of cannabis develops with use and the existence of a dependence syndrome is recognized. A recent study reported that cannabis users meeting criteria for dependence compared with those users not deemed to be cannabis dependent were more likely to have started using cannabis earlier, to have had fewer years of schooling and to consume more

Keywords cannabis; adolescence; outcome

Introduction As is evident from the media and the regular clinical experience of paediatricians and child psychiatrists, the use of illicit drugs and alcohol is widespread amongst adolescents and young adults in the UK and has lost much of the stigma with which it was previously associated. Cannabis is widely perceived as a safe drug in comparison with heroin or cocaine and until relatively recently was not believed to induce dependence or lead to a withdrawal syndrome. Its classification was downgraded from a Class B controlled drug to a Class C controlled drug in 2004. Data from the National Office for Statistics in 2004/5 show that in the UK 33% of males and 21% of females aged 16–24 years used illicit substances in the previous year, of which the majority were cannabis users – 30% of males and 18% of females in this age group. Whilst these figures might seem high, they represent a small decrease in cannabis use amongst 16–24 year olds since 1998.1 In addition, illicit drug use is not confined to middle or late adolescence; figures from 2000 suggest that 15% of boys and 13% of girls aged 11–15 years had used drugs in the previous year. Of those aged 11–15 years in England, 12% were using cannabis.1 A study published in 1996 of 7722 young people aged 15 and 16 years, at school in the UK, found that greater than 40% had

Anna Boyce MRPCH MRCPsych is a Specialist Registrar in Child and Adolescent Psychiatry, Young People’s Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK. Paul McArdle MRCPI MRCPsych DCH is a Consultant in Child and Adolescent Psychiatry, Fleming Nuffield Unit, Newcastle upon Tyne, UK.

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alcohol. Scores of happiness and life satisfaction were reduced in those who were cannabis dependent.7 Clear evidence of a cannabis withdrawal syndrome has been described with features of irritability, aggression, restlessness and strange dreams.8

The Dunedin Multidisciplinary Health and Development Study, a birth cohort study of 1037 individuals, collected data including self-reported psychiatric symptoms at age 11 years, cannabis use at 15 and 18 years and interview data leading to Diagnostic Statistical Manual (DSM) IV diagnoses at 26 years.12,13 Amongst those whose use of cannabis preceded the age of 15 years, there was an odds ratio of developing adult schizophreniform disorder of 3.1, after controlling for the presence of psychiatric symptoms at the age of 11 years. The review authors concluded that at an individual level cannabis usage doubled the relative risk for later schizophrenia. In addition, they concluded that at a population level, avoidance of cannabis use would lead to an 8% reduction in incidence of schizophrenia, and that whilst cannabis is ‘neither a sufficient nor a necessary cause for psychosis, it is a component cause, part of a complex constellation of factors leading to psychosis’.10 Participants in the Dunedin study were further studied to investigate the possibility that a gene–environment interaction might provide an explanation for the observation that only a minority of regular heavy cannabis users develop persistent psychotic symptoms.14 The investigators found that the effect of adolescent cannabis use was moderated by a functional polymorphism of the catechol-O-methyltransferase (COMT) gene, a gene on chromosome 22q11 in a region implicated by genome scans as having a possible aetiological role in schizophrenia. Using hierarchical regression analysis, the authors reported that the effect of genotype on psychotic symptoms was not significant, but the effect of cannabis use and the interaction between cannabis use and genotype were significant. In line with the hypothesis that cannabis use may have an effect on refinement of the mechanisms of dopamine transmission occurring during adolescence, the authors found that onset of cannabis use in adulthood was not associated with subsequent development of psychotic ­symptoms.

Issues complicating research into the long-term effects of cannabis Many of the studies from which the evidence relating to the longterm consequences of cannabis use has emerged are longitudinal studies recruited from the adult general population.9 The advantages of these cohort studies are the large number of participants and the capacity to detect adverse effects. Birth cohort studies, on the other hand, have the advantages of being able to investigate factors relating to early psychosocial- and neuro-­development and early onset of cannabis use, but have the disadvantage of being expensive, with lengthy intervals between commencement and eventual outcome. Ascertaining the causal role of cannabis use in adverse psychosocial outcomes is complicated by the potential confounding effects of multiple substance misuse, alcohol use, cigarette smoking, psychiatric disorders such as depression and anxiety and association with antisocial peer groupings. Reverse causation should also be considered, e.g. the use of cannabis as selfmedication for prodromal psychotic symptoms.10 Macleod et al9 set out systematically to appraise the evidence from longitudinal studies for a causal relation between cannabis use and psychosocial harm. They found 48 longitudinal studies, of which only 16 met their criteria for methodology and lack of significant bias. Three birth cohorts were included; the remaining studies were of school age cohorts. Outcome measures included antisocial behaviour, psychological functioning, subsequent illicit drug use and educational attainment. The authors commented that the variation in recruitment methods, methods of assessment of exposure to illicit substances and how confounding factors were taken into account precluded the use of meta-analysis. They concluded that there was reasonable evidence for associations between cannabis use and lower educational attainment and later use of illicit drugs, but argued that the evidence for associations between cannabis use and psychological health problems and behavioural problems was less robust. For instance, although ­ cannabis use may be ­associated with depression, third factors such as disturbed family life may explain both the use and the distress. Arseneault et al,10 in their review of the evidence for a specific link between cannabis use and risk of later psychotic symptoms, discuss the criteria by which causality can be inferred, such as association, temporal priority and direction (see below).

Other psychiatric and cognitive sequelae Cannabis use has been linked to symptoms of low mood and anxiety. Data from the Christchurch Health and Development Study were examined to ascertain associations between frequency of cannabis use and psychosocial outcomes, including depression, assessed using DSM criteria. Across the four age groups, 14–15 years, 15–16 years, 17–18 years and 20–21 years, the odds ratio for depression for weekly cannabis users relative to non-users was 1.7. With the exception of the age range 20–21 years, cannabis use was also significantly associated with rate of suicide attempts.15 A review of cohort studies,16 whose participants included adolescents and adults, concluded that there was a modest association between current heavy cannabis use and depressive symptomatology, and a modest association between early onset regular cannabis use and later depressive illness. No association was found between onset of depression and subsequent ­cannabis use. The same review found that early cannabis use may significantly increase the risk of leaving school early.16 Possible explanations are discussed, with reference to reverse causality, a specific ‘problem behaviour’ syndrome (likely to include the DSM IV concept of conduct disorder) of which substance misuse is one facet,

Cannabis use and risk of psychosis The findings of four major longitudinal studies, yielding much of the evidence for a causal association between cannabis use and psychotic illness, were reviewed in 2004 by Arseneault et al.10 One of these studies, the Swedish study of 50 000 army recruits,11 found a dose–response relationship between heavy cannabis use at 18 years of age and a subsequent diagnosis of schizophrenia within the 15 year follow-up period. This effect persisted after the confounding effect of pre-existing psychiatric diagnosis was controlled for, with a relative risk of 2.3.

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and the role of confounding factors. The authors make the point that it is unlikely that any single factor operates in isolation; rather the true picture may be a combination of many such processes. The relationship between educational attainment and cannabis use was also examined in the Christchurch Health and Development study;17 35.6% of young people who used cannabis on 10 or more occasions in the year between ages 15 and 16 years left school with no formal qualifications compared to 17.1% who had not used cannabis. The findings of this review are elaborated by those of a Canadian longitudinal birth cohort, the Ottawa Prenatal Prospective Study (OPPS).18 In this cohort 113 young people were tested at 9–12 years of age on measures of general intelligence, vocabulary, memory and sustained attention. Of this sample, 10 children had already tried cannabis, although none was using cannabis regularly at the time of testing. At the time period 17–20 years the cognitive tests were repeated. After exclusion of confounding factors, such as presence of psychiatric disorder and socioeconomic status, the current heavy use group had lower scores in measures of memory and IQ in comparison to the light use, former use and no use groups. No significant differences were found between the group of former cannabis users and the comparison group who had not used cannabis, suggesting that the poor educational attainment of young people using cannabis on a regular basis may be a direct consequence of recent cannabis use.

Effects of prenatal cannabis exposure Studies have failed to show an association between maternal cannabis use and low birth weight and low weight at 6 years.21,22 There is some evidence that prenatal exposure to cannabis may be associated with impaired attention in children. A study comparing the performance of 330 4-year olds with prenatal exposure to cocaine, marijuana, alcohol and tobacco found an association between heavy maternal marijuana use and omission rates on the Continuous Performance Test, suggesting a possible effect on sustained attention, although this finding did not reach statistical significance.23 Another study found an effect of prenatal marijuana exposure on attention in adolescents in one of five domains of attention.24 Exposure to prenatal illicit substances is a common component of background history in children assessed for adoption. It appears that, on the basis of available evidence, the effect of maternal cannabis use on a child’s later presentation is statistically detectable but modest. Prenatal cannabis exposure has also been implicated in the aetiology of childhood acute myeloid leukaemia (AML). A case– control study compared parental interview data of 517 children (maternal data available) and 450 children (paternal data available) with AML, with similar data from 610 and 523 controls, respectively. No positive association was found between parental marijuana use and childhood AML.25

Cannabis as a ‘gateway’ drug Long-term effects on physical health

An influential theory regarding the role of cannabis in the progression to further illicit substance misuse is the ‘stage theory’ of substance misuse, which supposes that young people proceed from using legal drugs such as alcohol to use of illicit drugs with cannabis use at an intermediate stage. Users of illicit substances are predicted to have previously used legal substances but not all of those who use legal substances will progress to use of illicit substances. Arguments against this theory include the possibility of confounding factors such as a predisposition to substance misuse or risk taking behaviour in general. By the age of 21 years, 70% of the Christchurch Health and Development Study cohort had used cannabis and 26% had used other illicit drugs.19 The vast majority of those who had used other illicit drugs had previously used cannabis. Using a form of multivariate analysis the investigators found that those who used cannabis on more than 50 occasions in a year had hazards of other drug use that were 140 times higher than those who did not use cannabis, after adjustment for confounding factors such as frequency of alcohol consumption and childhood sexual abuse. Inclusion of adverse life events and adolescent risk taking behaviour as co-factors in the model led to a reduction in hazards of other illicit drug use to 59 times higher than for non-users. A study of twins discordant for cannabis use, derived from the Netherlands Twin Register,20 examined subsequent progression to use of ‘party’ drugs and ‘hard’ drug use. In a sample of 219 twin pairs, average age 27 years, among whom only one twin had used cannabis before the age of 18 years and one subsequently, the odds ratio for ‘party’ drug use was 7.4 (confidence interval 2.3–23.4) and for ‘hard’ drug use was 16.5 (2.4–111.3), leading the authors to speculate that a factor directly related to cannabis itself might be at work.

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The effects of long-term cannabis exposure on the human respiratory system has been the focus of considerable research. A recent systematic review of clinical studies published between 1966 and 2005 found 34 studies meeting selection criteria.26 These could be subdivided into studies examining the short-term consequences of cannabis exposure on bronchodilation and studies of long-term smoking of marijuana and pulmonary function or respiratory symptoms. All 14 of the latter demonstrated association between cannabis use and respiratory symptoms, including cough, phlegm and wheeze. A cohort study of 53 controls and 188 subjects, of whom 40 were regular smokers of marijuana alone, 44 smokers of marijuana and tobacco and 31 smokers of tobacco only, who underwent bronchoscopy and endobronchial biopsy, found that smoking tobacco and marijuana were each associated with significant bronchial mucosal histopathology. The authors found that the effects of marijuana and tobacco on the bronchial mucosa were additive, including possible pre-malignant changes.27 Adverse effects on animal cellular immunity have raised question about the effects of cannabis use on the immune system. However, a review of animal and human studies concluded that there was no evidence of a significant effect in humans, with the exception of the effect of marijuana smoking on broncho-alveolar immunity.28

Substance misuse services for adolescents The UK government has recognized the need for the provision of substance misuse services for adolescents, and set out its agenda 39

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References 1 National Statistics website: www.statistics.gov.uk 2 Miller PMcC, Plant M. Drinking, smoking and illicit drug use among 15 and 16 year olds in the United Kingdom. BMJ 1996; 313: 394–397. 3 Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 2001; 178: 101–106. 4 Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998; 352: 1611–1616. 5 Mura P, Kintz P, Ludes B, et al. Comparison of the prevalence of alcohol, cannabis and other drugs between 900 injured drivers and 900 control subjects: results of a French collaborative study. Forensic Sci Int 2003; 133: 79–85. 6 Kalant H. Adverse effects of cannabis on health: an update of the literature since 1996. Prog Neuro-Psychopharmacol Biol Psychiatry 2004; 28: 849–863. 7 Looby A, Earleywine M. Negative consequences associated with dependence in daily cannabis users. Substance Abuse Treat Prev Policy 2007; 2: 3. 8 Wiesbeck GA, Schukit MA, Kalmijn JA, et al. An evaluation of the history of a marijuana withdrawal syndrome in a large population. Addiction 1996; 1: 1469–1478. 9 Macleod J, Oakes R, Copello A, et al. Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet 2004; 363: 1579–1588. 10 Arseneault L, Cannon M, Witton J, et al. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 2004; 184: 110–117. 11 Zammit S, Allebeck P, Andreasson S, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: a historical cohort study. BMJ 2002; 325: 1199–1201. 12 Arseneault L, Cannon M, Poulton R. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 2002; 325: 1212–1213. 13 The American Psychiatric Association. DSM-IV-TR: Diagnostic Statistical Manual of Mental Disorders. American Psychiatric Press Inc, 1994. 14 Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-o-methyl transferase gene: longitudinal evidence of a gene x environment interaction. Biol Psychiatry 2005; 57: 1117–1127. 15 Fergusson DM, Horwood LJ, Swain–Campbell N. Cannabis use and psychosocial adjustment in adolescence and young adulthood. Addiction 2002; 97: 1123–1135. 16 Degenhardt L, Hall W, Lynskey M. Exploring the association between cannabis use and depression. Addiction 2003; 98: 1493–1504. 17 Lynskey M, Hall W. The effects of adolescent cannabis use on educational attainment: a review. Addiction 2000; 95: 1621–1630. 18 Fried PA, Watkinson B, Gray R. Neurocognitive consequences of marihuana - a comparison with pre-drug performance. Neurotoxicol Teratol 2005; 27: 231–239. 19 Fergusson DM, Horwood LJ. Does cannabis use encourage other forms of illicit drug use? Addiction 2000; 95: 505–520. 20 Lynskey MT, Vink JM, Boomsma DI. Early onset cannabis use and progression to other drug use in a sample of Dutch twins. Behav Genet 2006; 36: 195–200. 21 English DR, Hulse GK, Milne E, et al. Maternal cannabis use and birth weight: a meta-analysis. Addiction 1997; 92: 1553–1560.

Figure 1 Cycle of change model.30

in the report Every Child Matters: Change for Children, Young People and Drugs.29 A useful framework for identifying appropriate timing of referral to specialist services, and as a method of engaging ­adolescents known to be involved in harmful use of illicit substances in the referral process, is provided by the cycle of change model described by Prochaska and Diclemente (­Figure 1).30 In this model an individual may be at any stage when they present. It should become apparent which stage they are at after an initial conversation about their drug use and their attitudes towards it. Clearly, referral of an individual contemplating change or already preparing to make changes in their drug use to the local substance misuse service is appropriate and should be done promptly. Individuals in the pre-contemplation stage may also benefit from referral, if only for discussion of the advantages and disadvantages of their drug use and education about harm minimization. Adolescents can be reassured about the confidentiality of such services (with the usual exceptions, e.g. child protection), although involvement and support of ­parents is encouraged.

Conclusion There is reasonable evidence for a link between cannabis use and risk of overall adverse psychosocial functioning, lower educational attainment, development of psychosis, particularly in individuals vulnerable by virtue of family history, and possibly cognitive performance. Young people using cannabis on a regular basis should be warned of the possible consequences to their mental health in addition to the physical health risks of smoking cannabis. Health professionals working with adolescents should be prepared to ask young people about their drug use and be aware of local resources to support young people who wish to address their drug use. ◆ PAEDIATRICS AND CHILD HEALTH 18:1

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22 Day NL, Richardson GA, Geva D, et al. Alcohol, marijuana, and tobacco: effects of prenatal exposure on offspring growth and morphology at age six. Alcohol Clin Exp Res 1994; 18: 786–794. 23 Noland JS, Singer LT, Short EJ, et al. Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol Teratol 2005; 27: 429–438. 24 Fried PA, Watkinson B. Differential effects of facets of attention in adolescents prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 2001; 23: 421–430. 25 Trivers KF, Mertens AC, Ross JA, et al. Parental marijuana use and risk of childhood acute myeloid leukaemia: a report from the Children’s Cancer Group (United States and Canada). Paediatr Perinat Epidemiol 2006; 20: 110–118. 26 Tetrault JM, Crothers K, Moore BA, et al. Effects of marijuana smoking on pulmonary function and respiratory complications. Arch Intern Med 2007; 167: 221–228. 27 Fliegel SE, Roth MD, Kleerup EC, et al. Tracheobronchial hisopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 1997; 112: 319–326. 28 Kraft B, Kress HG. Cannabioids and the immune system. Schmerz 2004; 18: 203–210.

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29 UK Government Department. Every Child Matters: Change for Children. Young People and Drugs. London: Department for Education and Skills, 2005. 30 Prochaska JO, Diclemente CC. Towards a comprehensive model of change. In: Miller WR, Heather N, eds. Treating addictive behaviours: processes of change. New York: Plenum Press; 1986, p. 3–27.

Practice points • Misuse of cannabis in adolescence may have long-term consequences on psychosocial functioning and mental health • Cannabis use is associated with later use of other illicit substances, although the mechanism for this is unclear • There is not enough evidence to enable prediction of outcome for individuals exposed to cannabis prenatally • Questions about substance misuse should form part of routine assessment by health professionals working with young people and referral to substance misuse services made as appropriate

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Personal practice

Headache in children and adolescents

Between headaches, she is back to her normal self and has no other illnesses. Laura and her mother are concerned about the headaches, their frequency and the number of school days lost due to headache. Physical and neurological examinations were normal.

Ishaq Abu-Arafeh

Key points in the history Children and their parents can often identify different types of headache experienced by the child. Laura was able to make a distinction between the severe headache episodes that she rightly described as migraine and other milder headache episodes that occurred more frequently. Unfortunately, other children may not be able to make this distinction. These children may describe the most severe attack, as it has made most impression on them and their family, or the most recent attack as it is still fresh in their minds. A prospective diary recording symptoms is a powerful tool in identifying the different types of headache, and may also help to identify triggers.

Abstract Headache is a common problem in children and adolescents. Migraine and tension type headache are most common causes of headache and only occasionally chronic headache is the main presenting feature of a serious brain disease or a brain tumour. Full clinical history, physical examination and headache diary recordings are essential requirement in the assessment of children with headache and the assessment of the impact of headache on child’s education, social and family life. Management of headache includes the promotion of healthy life style with regular meals, sleep and exercise. Painkillers are used in appropriate dose, as early as possible after the onset of headache and the use of most appropriate route of administration.

Interpretation of clinical history By making the distinction between the two types of headache, it was possible, on applying a recognized definition and dia­gnostic criteria, to establish the diagnosis of migraine without aura for the first type of headache, and frequent tension-type headache for the second. It should be remembered that migraine headache is commonly not lateralized in children, as in Laura’s case. The second edition of the International Classification of ­ Headache Disorders (2004) is an excellent resource for the definition of headaches in children and adults. Criteria for the diagnosis of migraine headache without aura and tension type headache are described in Tables 7 and 8, respectively, in the review by ­Mukhopadhyay and White elsewhere in this issue.

Keywords adolescents; children; migraine; tension-type headache

What do you do? Laura, a 12-year-old girl, attends the clinic with her mother complaining of headache for the past year. Laura and her mother describe two types of headache. The first type is a migraine ­occurring once a month. The attacks last for 24 h and the pain is severe enough to stop all activities. Laura describes the headache as throbbing with maximum intensity in her forehead. She can identify no trigger factors and has no warning signs before the onset of pain. The headache builds up in intensity over a period of 30–60 min and is almost always associated with loss of appetite, feeling sick, light intolerance, noise intolerance and pallor. In most, but not all, attacks she also vomits. She feels better after rest and sleep. Paracetamol helps a little, but she finds codeine most helpful in relieving symptoms. The second type is episodes of headache that occur at least three times per week and last between 2 and 3 h each. This headache does not stop normal activities and is described as ‘just sore’ around the head. There are no other associated symptoms and, in particular, she is able to have normal meals, has no feeling of sickness and does not vomit. Neither light nor noise bothers her during attacks. After an episode of throat infection, the headaches became daily for about 1 month and then reverted to the normal rate of occurrence of three per week. She finds relief from rest and she only occasionally treats these headaches with paracetamol.

Physical examination The negative findings in the physical examination and the ­neurological assessment are very important. They not only exclude the possibility of serious underlying disorder, such as a brain tumour, but also give the child and the parent the confidence that the doctor has taken their complaint seriously and looked for abnormal signs that may indicate a serious illness. Physical examination should include measuring the blood pressure and neurological assessment should include measuring head circumference, ophthalmoscopy and cerebellar function (looking for ataxia, nystagmus and intention tremor or point passing).

Investigations In the absence of symptoms suggesting increased intracranial pressure or signs suggesting cerebellar dysfunction, no further investigations are needed. A lower threshold for neuroimaging may be considered in: • children under the age of 5 years; • if in doubt about the physical findings; • cases of inconsistent features.

Ishaq Abu-Arafeh MBBS MD MRCP FRCPCH DCH is a Consultant Paediatrician, Stirling Royal Infirmary, Stirling, Scotland, UK.

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treatment. For effective pain relief, analgesics should be given in their optimum doses – 10–20 mg/kg for paracetamol and 10–15 mg/kg for ibuprofen. If simple analgesics are given in adequate dosage, there is seldom any additional benefit from using opiates such as codeine. In Laura’s case, by ensuring that her paracetamol dosage was adequate, she was able to discontinue the use of codeine. Oral administration of medications is the route preferred by most children and their parents, but if nausea and vomiting are early symptoms, oral medications are not effective. In such children, early treatment with an anti-emetic, such as cyclizine or metclopromide, may offer good relief of nausea and may improve the response to painkillers. In other children, the nasal route may offer a good alternative. Sumatriptan as a nasal spray (10 mg) is licensed for use in children over the age of 12 years and has been shown to be effective in many but not all patients.

Impact of headache on the child and family Although it is true that anxiety about possible intracranial pathology is an important reason for seeking medical advice, concerns about missing school and worries about the impact on the child’s education and enjoyment of family and social life are also important. The whole family becomes embroiled with the child’s symptoms, causing stress and anxiety to the rest of the family. Doctors need to enquire from the child and family what worries them most and to address these concerns in a direct and relevant manner, rather than confining the discussion to general reassurances on the benign nature of the disorder. In children with frequent headache, the help of an experienced clinical psychologist may prove most useful.

Advice and education The natural course of migraine is one of relapses and remissions. It is common for children to describe well-defined periods of high attack frequency separated by periods of relative remission. Good and bad spells of headache are often well recognized by patients and their parents. In many children it is not possible to identify a clear trigger for the bad spells, but in some anxiety and stress related to school exams and similar events are evident. It should be remembered that ‘exciting’ events, such as birthday parties, that may be seen in a positive light by the parents may be very stressful to the child. As they grow older children tend to have longer remissions (good spells), but unfortunately they continue to be prone to headaches and there is as yet no treatment that can be described as a cure for migraine. Similarly tension headache can recur after a period of remission. Children can reduce the frequency of headaches (both migraine and tension-type headache) and prolong the ‘good spell’ by adopting a healthy lifestyle. There is no single measure that is universally effective in migraine, but attention should be paid to the following: • regular meals; • regular sleep; • regular exercise and rest; • avoidance or at least reduction of exposure to caffeine­containing drinks; • avoidance of other xanthines such as chocolate; • avoidance of taking analgesics more than twice a week to ­prevent the emergence of overmedication headache. A carefully taken history may uncover triggers for the attacks and, of course, these should be avoided. However, these triggers are often rather vague and not easily avoided. Where stress is cited as a trigger, the help of a clinical psychologist may be enlisted.

Preventing migraine headache Preventative treatment of migraine is indicated if attacks occur on at least four occasions per month and are severe and long enough to stop activities, and when simple lifestyle measures are ineffective. There are no reliable medications to prevent headache in all children all the time, but pizotifen, propranolol and possibly topiramate are worth trying as they may offer relief to some children. Medication should be taken regularly for at least 2 months in appropriate dosages before its success or failure can be confidently decided.

Managing tension-type headache The management of tension-type headache can be tailored to suit the child. In many children the use of simple analgesics is safe and effective, and should be used early and in the full recommended dose. In other children, frequent tension-type headache can be transformed to chronic daily headache and becomes resistant to analgesia. In these cases, overmedication headache is a real risk and analgesia should be withdrawn in order to achieve resolution of the daily headache. The withdrawal of analgesia can cause apprehension and worry, and also a transient worsening of the headache. If children and their parents are properly warned of possible worsening of symptoms during the first week of withdrawal, the compliance with advice is usually good and improvement follows. ◆

Practice points • Headache and migraine are common in children and adolescents • Headache can cause disruption to the child’s schooling and social life • Different types of headache frequently co-exist in the individual child • Headache diaries are useful in making the diagnosis of different types of headache • Investigations are rarely needed in children with typical history and normal examination • Explanation of the diagnosis and education of the child and their family make compliance with advice and treatment easier

Managing migraine headache Children should be given the opportunity to lie down for rest and sleep if possible. Successful acute treatment of migraine attacks depends on the recognition of early symptoms and the administration of the most appropriate painkiller, in an appropriate dose and using the most appropriate route. There is a tendency for parents and primary care medical practitioners to administer small doses of analgesia, and also to delay administration of treatment until the headache is established and shown to be severe enough to warrant

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self-assessment

Self-assessment Questions

Creatinine Bilirubin Alkaline phosphatase GGT ALT Amylase CRP Calcium (corrected) Phosphate Blood sugar

Case 1 A 9-year-old boy presented to A&E with a 2-day history of double vision, squint (right eye) and headache. He had been apyrexial with no other symptoms. Past medical history was unremarkable. The observations were as follows: HR 80/min, RR 20/min and BP 120/75 mmHg. Examination was normal other than isolated 6th nerve palsy on the right side. 1. What is the likely diagnosis? Choose ONE answer ONLY from the following: A. Diabetic neuropathy B. Malignancy C. Multiple sclerosis D. Myasthenia gravis E. Meningitis 2. What investigation will you request? Choose ONE answer ONLY from the following: A. HbA1C B. Full blood count and blood film C. Lumbar puncture D. Tensilon test E. MRI scan of brain F. Bone marrow aspiration

3. What is your diagnosis? Choose ONE answer ONLY from the following: A. Viral hepatitis B. Autoimmune hepatitis C. Lymphoma D. Hepatoblastoma Case 2 A 4-year-old boy presented to his GP with a 5-day history of vomiting and was diagnosed with viral gastroenteritis. He improved temporarily over the next 2 days but needed hospital admission when the symptoms worsened. The child did not have any fever, diarrhoea or skin rash. He had not passed urine over the previous day. He had been in good health prior to this illness. On examination he looked unwell, sleepy and was dehydrated. His abdomen was soft and there was no organomegaly. Bowel sounds were normal. Observations were as follows: temperature 37° C, HR 130/min, RR 22/min, SaO2 100% in air, BP 89/57 mmHg and capillary refill time 3 s. He was administered a bolus of normal saline (10 ml/kg) and intravenous fluid was commenced to correct the deficit and provide maintenance. The blood results showed the following:

MRI of the brain was normal and the ophthalmologist suggested eye patching. Two weeks later the boy presented with nausea, vomiting and reduced appetite. He had seen the GP the previous week because of abdominal pain and constipation. On examination he looked unwell with a distended abdomen. A slightly tender mass was felt in the right hypochondrium extending 7 cm below the costal margin with a firm consistency and smooth contour. Bilateral inguinal lymphadenopathy was also noted. The full blood count showed:

Hb WCC Neutrophils Lymphocytes Platelets CRP Na K Urea Creatinine

Hb 10.9 g/dL (9.5–13.5 g/dL) WCC 10.7 × 109/L (4.5–13.0 × 109/L), Neutrophils 7.17 × 109/L (1.8–8.0 × 109/L) Lymphocytes 2.03 × 109/L (1.0–5.0 × 109/L). There were no blast cells on peripheral blood film Na K Urea

134 mmol/L (135–145 mmol/L) 4.6 mmol/L (3.8–5.5 mmol/L) 9.3 mmol/L (1.8–6.4 mmol/L)

13.4 g/dL (9.5–13.5 g/dl) 6.3 × 109/L (4.5–13.0 × 109/L), 4.1 × 109/L (1.8–8.0 × 109/L) 1.9 × 109/L (1.0–5.0 × 109/L) 369 × 109/L (170–400 × 109/L) <5 mg/dL 136 mmol/L (135–145 mmol/L) 4.4 mmol/L (3.8–5.5 mmol/L), 6.4 mmol/L (1.8–6.4 mmol/L) 52 μmol/L (20–74 μmol/L)

Liver function tests: Total bilirubin 6 μmol/L (0–17 μmol/L) ALT 5 IU (0–35 IU) Alkaline phosphatase 100 IU (110–270 IU) Total protein 62 g/L (64–83 g/L) Glucose 5.3 mmol/L Urine dipstick showed 2 + of ketones

Archana Joshi MBBS DCH MRCPCH is a Specialist Registrar in Paediatrics at the Lister Hospital, Corey’s Mill Lane, Stevenage, Herts SG1 4AB, UK. Basheer P Mohamed MBBS MRCPCH is a Specialist Registrar in Paediatrics at the Lister Hospital, Corey’s Mill Lane, Stevenage, Herts SG1 4AB, UK. Jonathan Kefas MB DTCH MRCPCH is a Consultant Neonatologist at the Lister Hospital, Stevenage, Corey’s Mill Lane, Herts SG1 4AB, UK.

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107 μmol/L (20–74 μmol/L) 17 μmol/L (0–17 μmol/L) 566 IU (110–270 IU) 649 IU (5–32 IU) 150 IU (10–35 IU) 225 IU (28–100 IU) 6 mg/dL 2.7 mmol/L (2.15–2.60 mmol/L) 1.46mmol/L (1.10–1.80 mmol/L) 4.7 mmol/L

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self-assessment

1. What is the likely diagnosis? Choose ONE answer ONLY from the following: A. Viral gastroenteritis B. Intussusception C. Appendicitis D. Inflammatory bowel disease

bilateral weakness of extraocular eye movements. Meningoencephalitis can cause cranial nerve palsy, but it is unlikely in the absence of other clinical signs of infection, as in this case. Therefore, a malignant or an infiltrative process is the most likely diagnosis. 2. E Isolated 6th nerve palsy (one or both) is a relatively common feature of generalized increase of intracranial pressure. Nonsolid tumours such as leukaemia can impair the reabsorptive mechanism in the subarachnoid space leading to increased intracranial pressure and sometimes hydrocephalus. Therefore, neuroimaging should be performed urgently. MRI is better than CT scan for infratentorial lesions. Lumbar puncture should not be performed without ruling out raised intracranial tension.

He continued to vomit following admission and his observations overnight were as follows: HR 65/min, RR 26/min, BP 125/80 mmHg, SaO2 89% in air, overnight urine output 2.3 ml/kg/h. 2. What is your diagnosis? A. Haemolytic uraemic syndrome B. Intracranial space occupying lesion C. Superior sagittal sinus thrombosis D. Diabetic ketoacidosis

3. C Acute lymphoblastic leukaemia and non-Hodgkin lymphoma (non-solid tumours) can present with neurological signs. Viral and autoimmune hepatitis may rarely be associated with neurological features, especially isolated cranial nerve palsies. Hepatic tumours are rare in children. Metastasis from other common childhood malignancies should always be ruled out. Hepatoblastoma generally presents in the first 18 months of life as an asymptomatic abdominal mass with other features like abdominal pain, vomiting, weight loss and metastasis occurring later.

Case 3 A 10-year old girl was brought to A&E by grandparents late in the evening, as they were unable to cope with the child’s loss of appetite and nausea. The child had recently lost her mother and the whole family was grieving. Further inquiry revealed a history of occasional vomiting, headaches and weight loss. She had been a fit and healthy child previously. A brief examination done by the doctor was normal. The girl was cooperative but wanted to go home to her bed. Hence the doctor sent the child home but with a plan for admission to the ward the next day.

Case 2 1. A Intussusception is unlikely in the absence of abdominal pain and diarrhoea (note: the classic redcurrant jelly stool is usually a late sign). Appendicitis is usually diagnosed from the right iliac fossa tenderness and guarding. Inflammatory bowel disease has a more insidious onset with diarrhoea, weight loss, loss of appetite and raised inflammatory markers.

1. What is the most likely diagnosis? Choose ONE answer ONLY from the following: A. Depression B. Anorexia nervosa C. Malignancy D. Bulimia She was admitted to the ward the next day and a detailed clinical examination revealed loss of pupillary light reflex with upward gaze palsy and nystagmus on attempted upward gaze.

Answers

2. B This patient presented with classical features of Cushing’s reflex – hypertension and bradycardia – which is seen in raised intracranial pressure. Abnormal breathing pattern (Cheyne– Stokes breathing) is part of the triad of symptoms. Superior sagittal sinus thrombosis should be considered in any child with severe dehydration and evolving neurological symptoms. Absence of tachycardia and a good urine output indicates a well-hydrated child. Haemolytic uraemic syndrome presents with anaemia, thrombocytopaenia and impaired renal function. Diabetic ketoacidosis is unlikely given the normal blood glucose. In this case, an urgent MRI was performed, which revealed a medulloblastoma.

Case 1 1. B Diabetic neuropathy and multiple sclerosis are unlikely to present at this age, although they should be considered in the differential diagnosis. Myasthenia gravis presents with

Case 3 1. A Depression is often under diagnosed in children. It may be precipitated by changes in body, roles and relationships. Furthermore, bereavement is an important cause of major depression.

2. What is the clinical feature described? Choose ONE Answer ONLY from the following A. Horner syndrome B. Trochlear nerve palsy C. Parinaud syndrome D. Oculomotor nerve palsy

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self-assessment

Depressed mood, weight loss or gain, insomnia or hypersomnia, fatigue, feeling of worthlessness or guilt are features of depression. When these symptoms occur within 3 months of an identifiable stressor, this is considered as adjustment disorder with depressed mood. Anorexia nervosa is a ­psychiatric disorder characterized by intense fear of becoming obese, altered self perception of body image and refusal to maintain body weight over a minimal normal weight for age and height. Bulimia is defined as a separate clinical entity by DSM IV ­criteria with the following features: recurrent episodes of binge eating and fear of not being able to stop eating during a binge, and regularly engaging in activities such as self-induced vomiting, abuse of laxatives, rigorous exercise which counteracts the effects of binge eating. Eating disorders are commonly seen in the 16–18 year age group and more commonly involve girls than boys. The incidence is on the rise in all western countries. Malignancy should be considered in the differential diagnosis of weight loss in children and hence a full clinical examination is vital, before a diagnosis of non-organic cause is made.

features include supranuclear palsy of upward gaze with preservation of downward gaze, loss of pupillary light reflex and nystagmus on attempted upward gaze. This child was diagnosed with pinealoma. A pineal tumour compressing the anterior hypothalamus causes loss of vision, diabetes insipidus, precocious puberty, emaciation (diencephalic syndrome) and sometimes obesity from insatiable appetite. Horner syndrome results from cervical sympathetic chain injury and comprises ptosis, miosis, anhydrosis and enophthalmos. Ptosis in Horner’s syndrome is often incomplete, whereas in 3rd nerve palsy there is complete ptosis along with mydriasis. There is inability to elevate and adduct the eye. Trochlear nerve palsy, on the other hand, results in paralysis of the superior oblique muscle and hence causes difficulty with looking down and in. Children typically present with a head tilt and face turned towards the unaffected side.

Further reading Fenichel GM. Clinical Pediatric Neurology: A Sign and Symptoms Approach, 5th edn. Philadelphia: WB Saunders, 2005. Kleigman RM, Behrman RE, Jenson HB, Stanton BF eds. Nelson’s Textbook of Pediatrics, 18th edn. Philadelphia: WB Saunders, 2007.

2. C The clinical features are consistent with a condition referred to as Parinaud syndrome, which is due to mid-brain dysfunction resulting from pressure by pineal tumours. The clinical

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