ARTICLE IN BRIEF
A panel of experts advises that patients who have a cerebral cavernous malformation (CCM) and experience a seizure should be referred to a specialist with training and expertise in epilepsy to assess whether the patients' seizures are causally related to the CCM.
Patients with cerebral cavernous malformations (CCMs), who experience a first seizure, should be carefully screened by an epileptologist familiar with imaging and surgical options, according to recommendations by the Surgical Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy (ILAE). The ILAE, an international association of physicians and other health professionals dedicated to improving education and research on diagnosing and treating epilepsy, has proposed a new definition of epilepsy, as well. [See “The ILAE Proposes ‘New’ Definition of Epilepsy.”]
Many patients with CCM who undergo surgical resection do not achieve postoperative seizure freedom, according to the report, because efforts to define and resect the epileptogenic zone are currently insufficient.
“This is the most comprehensive review to date,” said principal investigator Felix Rosenow, MD, professor of neurology at the University Hospital and Philipps-University in Marburg, Germany, and head of the university's Epilepsy Center in Hessen.
“Presently, only 70 percent of patients with malformations achieve seizure-free status. This should be 90 percent,” he told Neurology Today in a telephone interview. “The question is why are the surgical procedures currently performed on 20 percent of these patients not eliminating their seizures?”
The ILAE reviewed the current literature on CCM-related epilepsy (CRE), dividing patients based on symptoms and the confirmed presence of cavernomas. Their recommendations on diagnostic evaluation and etiology-specific management were published in the December 2013 issue of Epilepsia.
The report classifies definite CRE as seizures in patients with at least one CCM and evidence of a seizure-onset zone in the immediate vicinity. Probable CRE includes patients with at least one CCM and evidence that the epilepsy is focal and from the same hemisphere as the CCM, but not necessarily in its immediate vicinity and without evidence of other causes for seizures. CCM unrelated to epilepsy is defined as evidence that the CCM and epilepsy are not causally related.
Dr. Rosenow said that the panel's most important recommendation is that all CCM patients with a first seizure should be referred to a specialist with training and expertise in epilepsy to assess whether the patients' seizures are causally related to the CCM. Imaging should include MRI gradient echo or susceptibility weighted sequencing, with follow-up imaging after six months, and at yearly intervals thereafter or sooner if a patient develops new neurological symptoms.
If surgery is indicated, it is important that the neurosurgeon understands how and when CCMs should be excised. Vascular surgeons often address CCM-related bleeds rather than the epilepsy, the panel noted.
Dr. Rosenow said that the researchers are considering conducting a prospective trial to see if immediate surgery might result in better outcomes than delaying procedures, adding that such a trial would take between eight and ten years.
Of special interest is whether excision margins should include areas bordering malformations characterized by hemosiderin deposits indicative of bleeding. Although one study at four centers suggested that resection might help, there is not enough evidence to warrant excision of the fringe, Dr. Rosenow said.
“There are no neurons in the cavernomas, therefore they are not causing the seizures, so it must be the surrounding cortical gliotic tissue,” he said. “We recommend resection of at least the cortical parts of the surrounding gliotic hemosiderin-stained tissue whenever possible without causing deficits.”
Such surgery is not without risk however. Research suggests that between 12- and 17-percent of patients may develop neurologic symptoms following surgery, including sensorimotor deficits and homonymous hemianopia or quadrantanopia immediately after an operation. Other symptoms may include severe headache, slight dysphasia, sensory disturbances, ataxia, severe hemiparesis, and pontocerebellar degeneration.
DIAGNOSIS, TREATMENT RECOMMENDATIONS
The ILAE made several specific findings about the diagnosis and treatment of CCM in epilepsy patients. The researchers noted that some studies have suggested that repeated microbleeds and hemosiderin deposits in surrounding cortical tissue may cause hyperexcitability. But they wrote that hemosiderin deposits may only indicate that damage has occurred rather than being the main contributor to the development of epilepsy; they noted that astrogliosis and albumin leakage may also play a role.
In addition to gradient echo MRI, the report said that other helpful diagnostic imaging may include susceptibility weighted imaging, magnetization-prepared rapid gradient-echo, fluid-attenuated inversion recovery, and T2 turbo-spin echo sequences.
Diagnosis and treatment should be based on the symptoms and evaluation of each individual patient, the report said — for example, if they have no seizures, new-onset seizures, drug-responsive or drug-resistant seizures, multiple cavernomas, or dual pathology. Microsurgery is considered the safest and most effective therapy for drug-resistant epilepsy patients with CCM. The dosing and efficacy of radiosurgery remain unclear, but it may be an alternative for such patients.
The panel found too little evidence to reach any recommendation about resecting surrounding gliotic hemosiderin-stained tissue, but it recommended resecting at least the cortical parts of the hemosiderin rim, whenever possible, without causing deficits.
RANDOMIZED TRIALS NEEDED
Rustam Al-Shahi Salman, PhD, professor of clinical neurology at the University of Edinburgh in the UK, noted that the ILAE paper is a very good summary of what is known to date about seizures and CCMs and is consistent with the ILAE's new definition of patients with epilepsy.
“The first step, however, is to gather good evidence that can improve and inform clinical practice,” he told Neurology Today in a telephone interview.
“To my knowledge, there have not been any randomized trials comparing medical management with antiepileptic drugs against the two most widely used approaches to treatment — microsurgery or stereotactic radiosurgery. Because the few comparative observational studies that have been done have not shown large differences between them, future guidelines will require randomized trials.”
In the absence of randomized trials, variation in how clinicians treat CCM in patients with epilepsy is likely to continue, he said, adding that one of the controversial issues is how to treat CCM patients who have persistent seizures after the failure of the second antiepileptic medication.
“Generally, the patients are referred for microsurgical resection, but we need to know if simple lesionectomy is effective, of if more extensive resection of the hemosiderin ring and adjacent brain parenchyma should be recommended. This paper correctly recommended a trial to sort this out.”
However, Dr. Salman took issue with the ILAE recommendation that patients undergo follow-up imaging on an annual basis.
“Studies have not examined the value of annual MRI for these non-neoplastic vascular malformations,” he said. “Annual MRI has the potential to provide false reassurance or cause anxiety for patients. I feel that repeat imaging is only necessary if there is diagnostic doubt, or if a patient has new symptoms relating to the CCM.”
Jacqueline French, MD, professor of neurology at New York University and co-director of Epilepsy Research and Epilepsy Clinical Trials at New York University's Langone Medical Center's Comprehensive Epilepsy Center, said that many CCM procedures in epilepsy patients are currently being done by neurosurgeons lacking training in epilepsy surgery.
“Not all of these procedures are being done at academic or epilepsy centers, and each patient is different. You must know where the seizures are coming from and understand each individual's epilepsy before undertaking resection, and that requires someone trained in epilepsy,” she told Neurology Today in a telephone interview.
“Giving rules that simply say, ‘cut here’ will not resolve this question,” said Dr. French, who serves on the editorial advisory board of Neurology Today.
THE ILAE PROPOSES ‘NEW’ DEFINITION OF EPILEPSY
Two unprovoked seizures within 24 hours has been the benchmark definition of epilepsy, but the International League Against Epilepsy (ILAE) has determined that this may be inadequate in some clinical circumstances. A single seizure can now define epilepsy in people with factors that are associated with a very high likelihood of a persistently lowered seizure threshold, such as remote structural lesions caused by stroke, CNS infection, and certain types of traumatic brain injury. This risk should be equivalent to the recurrence risk of a third seizure in those with two unprovoked seizures, or approximately 75 percent, the ILAE panel said.
The ILAE also noted that epilepsy should be considered “no longer present” if a person has been seizure-free for at least 10 years after stopping antiepileptic medications; has no known ongoing predisposition to seizures; or has passed the age of an age-dependent epilepsy syndrome. However, because there are so few detailed studies on seizure recurrence risk, most diagnoses will still be made by documentation of two unprovoked seizures, the ILAE panel concluded.
The ILAE proposal for a new definition of epilepsy is available here: http://bit.ly/1lD4VRs. See an upcoming issue of Neurology Today for commentary from experts on this and other evolving definitions of neurological conditions.