Published 21 October 2009, doi:10.1136/bmj.b4133
Cite this as: BMJ 2009;339:b4133

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Picture Quiz

Seizures in a 9 month old girl

¹ Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ

A 9 month old girl presented to hospital in status epilepticus. Seizures were focal, affecting the right side, with secondary generalisation. She had no history of seizures. She was known to have an asymptomatic cardiac rhabdomyoma in the region of the left ventricular outflow tract. This had been diagnosed during investigation of a cardiac murmur detected during routine newborn examination. Her neurodevelopment was normal. Computed tomography was performed after resuscitation and stabilisation (fig 1).

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1 Computed tomogram of the brain

Questions

1 What are the major abnormalities shown on the computed tomography scan?

2. On the basis of these appearances and the medical history, what is the underlying diagnosis?

3 How should seizures associated with this condition be managed?

4 What is the neurodevelopmental prognosis for the child?

Answers

Short answers:

1 The computed tomogram shows multiple areas of low attenuation in the subcortical and deep white matter, and discrete foci of subependymal calcification.

2 Tuberous sclerosis.

3 Status epilepticus should be treated acutely with benzodiazepines and phenytoin. Focal seizures should be treated with carbamazepine, whereas infantile spasms should be treated with vigabatrin.

4 Tuberous sclerosis can be associated with significant learning difficulties and later with neuropsychiatric problems.

Long answers
1 Major abnormalities on computed tomography

The computed tomography scan is consistent with the appearance of cortical tubers and subependymal nodules, as found in tuberous sclerosis (fig 2). Cortical tubers are non-malignant lesions that consist of disorganised large cells resembling astrocytes. Subependymal nodules are hamartomas that form on the wall of ventricles. These nodules usually calcify and are thought to be precursors of giant cell tumours, which although benign may cause a mass effect or obstruction of cerebral spinal fluid flow (or both).

View larger version (41K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2 Computed tomography image of the brain showing calcified subependymal nodules (white arrows) and multiple areas of low attenuation in the deep subcortical white matter (grey arrows) representing cortical tubers

 
2 Underlying diagnosis
The patient fulfils the diagnostic criteria for tuberous sclerosis (box).¹ Tuberous sclerosis affects around one in 6000 people in the United Kingdom.² Inheritance is autosomal dominant, although most cases are caused by new mutations. Two genes have been identified—tuberous sclerosis complex 1 (TSC1) and TSC2. One of these genes is deleted in around 85% of patients. De novo TSC2 deletions are associated with a more severe clinical phenotype than are deletions of the TSC1 gene.³

Diagnostic criteria for tuberous sclerosis1    Major Facial angiofibroma Ungual fibroma Shagreen patch Hypomelanotic macule Cortical tubers Subependymal nodule Subependymal giant cell tumour Retinal hamartoma Cardiac rhabdomyoma Renal angiomyolipoma Lymphangiomyomatosis    Minor Multiple pits in dental enamel Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Retinal achromic patch Tumour "confetti" skin lesions Multiple renal cysts Non-renal hamartoma Diagnosis of "definite" tuberous sclerosis requires two major features or one major and two minor features. "Probable" tuberous sclerosis requires one major plus one minor feature

The presence of cardiac rhabdomyomas in isolation is not diagnostic but is strongly predictive of tuberous sclerosis.⁴ Rhabdomyomas may cause rhythm disturbance including tachyarrhythmias, heart block, and Wolf-Parkinson-White syndrome. Up to 70% of infants with tuberous sclerosis have rhabdomyomas,⁵ but most lesions regress spontaneously without symptoms.⁶

Infantile spasms are the neurological hallmark of tuberous sclerosis, although all seizure types can occur. Affected people have an 80% lifetime risk of seizures.⁷ Tuberous sclerosis is associated with many other neurological conditions, including pervasive developmental disorders, affective disorders, and learning disability.

3 Management of seizures
Tuberous sclerosis is associated with a wide range of seizure types. Status epilepticus should be treated with benzodiazepines followed by intravenous phenytoin.⁸ Focal seizures should be treated with carbamazepine, but may also respond to vigabatrin, lamotrigine, or topiramate.² The first line treatment for infantile spasms is vigabatrin, which inhibits the catabolism of the neurotransmitter GABA (-aminobutyric acid).⁹ Meta-analysis suggests a clinical response of greater than 90%.¹⁰ Visual field defects are a common side effect in adults, but these cannot be reliably measured in children.¹¹ Patients who do not respond to vigabatrin can be treated with steroids (prednisolone or adrenocorticotrophic hormone).¹² Patients with drug resistant epilepsy may benefit from a ketogenic diet or surgical resection of epileptogenic tubers.^{13 14}

4 Neurodevelopmental prognosis
The neurodevelopmental outlook for patients with tuberous sclerosis is variable. Studies show a bimodal distribution of IQ. Almost 50% of patients have a learning disability (IQ <70), and many are profoundly disabled (IQ <21).⁷ Intellectual impairment in tuberous sclerosis is independently associated with the presence of seizures, and with infantile spasms specifically.^{7 15} IQ is also inversely related to the number of cortical tubers.¹⁵

Effective seizure control is essential in the management of tuberous sclerosis. The degree of learning disability has been shown to be associated with the duration of infantile spasms and poor control of other seizure types.¹⁶ Developmental regression may occur in patients under the age of 5 years with poorly controlled seizures.¹⁷ Current recommendations therefore support aggressive management of seizures in infancy.¹¹

Tuberous sclerosis is associated with several neuropsychiatric disorders. Autism is especially prevalent—it affects 16-50% of patients with the condition.^{18 19} The development of autism is related to cortical dysfunction and is found almost exclusively in patients with seizures and low IQ.²⁰ A recent study showed the combined incidence of psychopathology to be 45% in adults with tuberous sclerosis.²¹

Tuberous sclerosis is a multisystem disorder. Management should focus not only on the physical effects of the condition but also on the psychological effect on patients and their families. Useful information for clinicians, patients, and their families can be found at the website of the UK Tuberous Sclerosis Association (www.tuberous-sclerosis.org).

Patient outcome

The patient made an uneventful recovery and was discharged home on vigabatrin. She has had four subsequent admissions with prolonged focal seizures and has had sodium valproate added to her maintenance treatment.

Cite this as: BMJ 2009;339:b4133

Provenance and peer review: Not commissioned; externally peer reviewed.

Parental consent obtained.

References

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