By Prakash Kotagal, MD
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At age 4, “Jason” began having seizures that consisted of waking up screaming and with right leg stiffening. In rare instances, this progressed to a generalized tonic-clonic convulsion. Seizures stopped with valproate treatment.
At age 5, over a period of three or four months, Jason went from having intact language to loss of language skills. He stopped understanding routine words and commands, expressing himself only with gestures and unintelligible sounds. He appeared not to hear and ignored people calling him or noises such as the doorbell. His behavior notably regressed.
Discussion: Cause of aphasia?
Sometimes developmental regression results from worsening seizures, but Jason’s seizures were under good control. New-onset aphasia may also result from excessive interictal EEG spiking in the language-dominant posterior temporal region, with resultant auditory agnosia. The constant spiking interrupts the function of auditory association cortex, rendering the child unable to interpret the sounds around him.
This phenomenon, referred to as Landau-Kleffner syndrome, is most commonly seen in the setting of benign focal epilepsy of childhood. In such cases, the idiopathic epilepsy may be benign in that seizures are infrequent and the condition is self-limited to childhood, usually resolving by age 14. But it is not always benign in the sense of being harmless. The language deficit due to constant interictal spiking may be severe and, if left untreated, partially irreversible when the spiking eventually resolves.
EEG is the key to diagnosis.
Awake EEG (image below) revealed prominent continuous slowing in the left hemisphere with occasional sharp waves in the left temporoparietal region.
Sleep EEG (image below) was reported as electrical status epilepticus during sleep (ESES) and showed high-amplitude spiking occurring in 80 percent of slow-wave sleep in the left language-dominant hemisphere in the posterior temporoparietal region.
MRI showed a left middle cranial fossa arachnoid cyst (image below) on the same side as the EEG spiking. The cyst did not appear to have a mass effect and had no heterogeneous component, which gave it a low likelihood of being a tumor.
Landau-Kleffner syndrome diagnosed
Jason’s EEG during sleep confirmed a classic presentation of Landau-Kleffner syndrome. A rare disorder, it usually appears between ages 3 and 7 years with epilepsy and either sudden or gradual onset of aphasia. Because of the auditory agnosia, children may behave as if they are deaf, although hearing is actually intact.
The EEG is characteristic: First described in 1975, the syndrome was defined as having high-amplitude discharges in the left posterior temporal region during more than 85 percent of sleep. That threshold is no longer considered critical; if clinical features are also present, the diagnosis can be made with spiking as little as 50 percent of the time, especially if spiking occurs during slow-wave sleep.
Landau-Kleffner syndrome differs from other “excessive spiking syndromes” such as ESES or “electrographic status epilepticus in sleep,” also known as CSWS for “continuous spikes and waves during slow sleep.” In Landau-Kleffner syndrome, the focus of the discharges in the language area is a prominent feature. In contrast, diffuse or bilateral CSWS may present with epileptic encephalopathy and is less specifically language-related.
Case continued — a rocky course
Clonazepam was added to valproate, and Jason improved, but only temporarily. As his symptoms recurred and progressed, he was started on IV methylprednisolone for five days and then oral prednisone for three months. This resulted in marked improvement in language, school performance and behavior.
Over the next year, Jason’s language regressed with every attempt to wean him from steroids. He developed cushingoid features, weight gain, difficulty climbing stairs and insomnia as side effects of therapy. His behavior worsened.
After six months of oral steroids, spikes were reduced but still occupied 50 percent of sleep recordings. At age 7, Jason started having a new type of seizure two or three times a week, consisting of staring, unresponsiveness and falling. He became withdrawn. Levetiracetam and clobazam were added to valproate, without effect. A different treatment paradigm was needed.
The literature reports that IV immunoglobulin (IVIG) benefits a subset of patients with Landau-Kleffner syndrome or CSWS. IVIG contains nonspecific antibodies with multiple effects, and it is unclear exactly how it confers clinical benefit. It is generally a safe alternative to steroids, although some patients develop an allergic reaction, and side effects can include headache, flushing, myalgia and, in rare cases, inflammatory meningitis. For immune-modulating therapy, dosing is 1 to 2 g/kg.
Jason started IVIG treatments, and prednisone was slowly weaned over the next five months. He became more alert, and his language and behavior improved.
Jason is now 8 years old and has had 15 months of monthly IVIG therapy. He is off steroids, and his muscle strength has returned. His parents report that his language is back to normal, he is at grade level in school and he acts like other children his age. He remains on valproate and levetiracetam and is without seizures. No epileptiform discharges were found on an ambulatory EEG over a 24-hour period.
His parents ask about stopping therapy. There is little experience in the literature regarding ending IVIG therapy for children with Landau-Kleffner syndrome who respond to it. It seems prudent to complete a two-year course (as is done with epilepsy medications) and then either start to extend the periods between treatment or end treatment abruptly, depending on family wishes and the clinical picture.
Reflections on managing Landau-Kleffner
Landau-Kleffner syndrome is an infrequent cause of epilepsy in children but an important one to recognize because treatment can make a big difference to language and other outcomes. It is classified as an “electroclinical” syndrome and could have many etiologies. Once discovered, a search should be made for a lesion, genetic condition, metabolic syndrome or other cause.
It’s possible that the subarachnoid cyst seen on MRI played a role in this case, and that epilepsy surgery could be a consideration if needed. But because the child responded well to medical treatment, a wait-and-see approach was justified.
A pooled analysis of 575 cases of ESES (Epilepsia. 2015;56:1738-1746) found that about one-third had improved cognition and EEG with standard antiepileptic drugs, as did almost 60 percent with benzodiazepines, 75 percent with steroids and 93 percent with surgery (including only a subset of children with lesions amenable to operation). Medications are typically tried in a stepwise manner.
When treating with steroids, it is thought that a high dose is better initially to try to suppress the immune system and hope that it remains quiet. After three months, a maintenance dose of 5 mg/day for a young child is appropriate. As in this case, adverse effects limit long-term treatment.
What if IVIG had not worked? There is some experience with treating Landau-Kleffner syndrome with surgery, even without a lesion. Subapial transection has met with some success in select patients, although its role is controversial. It involves cutting horizontal intracortical fibers (attributed to seizure transmission) while preserving vertical fiber connections (essential for function).
Dr. Kotagal is a pediatric epileptologist in Cleveland Clinic’s Epilepsy Center.
To view a webcast of this and nine other epilepsy cases in the “Hot Topics in Epilepsy for Children and Adults” CME-certified webcast series, visit ccfcme.org/EpilepsyCME. This activity has been approved for AMA PRA Category 1 Credit™.