Febrile Seizures: Evaluation and Treatment

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.