Antiepileptic Drugs (AEDs)
Most doctors require individuals with HH to start their treatment plan with antiepileptic drugs (AEDs) as it is the least invasive option. While some AEDs can control some types of seizures, seizure freedom or even good seizure control can be difficult to achieve for HH patients despite the use of higher doses and several combinations of antiepileptic drugs.
Gelastic seizures associated with hypothalamic hamartomas are generally resistant to medication. At this time, there does not appear to be one specific AED that is able to stop or even reduce gelastic seizures for the long term. However, the AEDs can be helpful in controlling the secondary seizures (absence, complex partial, and generalized) that often occur with HH. The decision regarding which drugs to try first and whether to try one drug at a time, or more than one at a time, is a difficult one. Some AEDs commonly reported by HH patients include valproic acid (Depakote), levetiracetam (Keppra), lamotrigine (Lamictal), carbamazepine (Tegretol, Carbatrol), topiramate (Topamax), and oxcarbazepine (Trileptal). Also, it can take a few weeks or even months to get to an appropriate dosage of the AED to determine its efficacy. However, there are other AEDs in use today that may be prescribed.
Many individuals experience side effects from the drugs including cognitive impairment, fatigue, depression, drug interaction, mood swings, and loss of concentration and focus. Some individuals may experience a “honeymoon effect” where the drugs seem to be working and then lose their effectiveness for no apparent reason. Some parents have reported that their kids seem to cycle with their seizure frequency, with days or weeks of high frequency followed by days or weeks of very few seizures, regardless of medication dosage. This can lead to the belief that frequent dosage changes must be made, further complicating the treatment plan. Doctors will typically recommend adjusting dosages or stopping drugs slowly over time to minimize potential side effects.
When considering surgery as a treatment option, it is important to consider all the benefits and risks. Decisions about proceeding with a more invasive treatment must always be highly individualized. For infants and young children with only gelastic seizures, the decision to “watch and wait” may be the most comfortable decision for some families. However, it is important to understand that studies have found that 50% of children with only gelastic seizures in the early years will develop the deteriorating form of the HH syndrome (loss of developmental milestones and progressive impairment of learning and cognition) and that up to 75% to 100% will develop other seizure types in their lifetime. Further research needs to be done comparing the outcomes of individuals who choose to intervene early versus those who delay.
All surgical approaches should be preceded by a detailed preoperative evaluation. The evaluation normally includes assessment of cognitive deficits, behavior disturbances, seizure severity, and the HH classification or type.
Several successful surgical approaches are now being used which allow for complete removal or partial resection and disconnection of an HH. With the advances in surgical techniques and experience, many HH treatment centers are recommending early intervention based on quality of life comparisons. For a list of questions to ask your surgeon if you are contemplating HH surgery, click here.
These surgical approaches include: a) Transcallosal anterior interforniceal approach (TAIF); b) Endoscopic resection/disconnection; and c) Orbitozygomatic approach. In some cases, surgeons have elected to do a combination of these approaches. The choice of the surgical approach is based upon the anatomy of the HH lesion of each patient.
Transcallosal Anterior Interforniceal Approach
Surgical options for HH patients took a giant step forward in 2001, when Dr. Jeffrey Rosenfeld of Melbourne, Australia, developed a new surgical approach to the hypothalamic hamartoma. His approach is known as the Transcallosal Anterior Interforniceal Approach. It is often the approach of choice for a larger HH. Most HHs are attached to one or both sides of the hypothalamus and protrude into the third ventricle, making them accessible for resection or disconnection via this approach. The main advantage of this approach is the excellent surgical view provided. A second advantage is the ability to resect (remove) and/or disconnect the HH and minimize injury to the mammillary bodies and other critically important structures that reside underneath or adjacent to the HH tumor. By approaching from above, there is less risk to the major blood vessels and cranial nerves at the base of the brain.
Seizure reduction after surgery has been very promising with this approach. In addition to a reduction in seizure frequency after resection, significant improvements in behavior, reduced aggression, increased concentration, and improved mood have been reported.
Complications have been reported with the transcallosal approach. In a few cases, when attempting a complete removal of the HH, injury to the hypothalamus has occurred. One of the more common complications is diabetes insipidus (DI). With DI, the kidneys are unable to conserve water and symptoms include excessive thirst and excessive urine output. DI can be successfully treated by a nasal spray (desmopressin, also known as DDAVP) administered one or more times a day. In most cases this condition resolves itself, while in some it has to be treated long term.
Another common complication after surgery is difficulty with short-term memory. The published research studies have reported that short-term memory issues are common. These resolve over time (usually days or weeks post-surgery) in most patients, but short-term memory impairment may be permanent in 10% of patients. (It is important to be aware that most HH patients have short-term memory problems even prior to surgery.)
A commonly encountered problem (10-20%) is increased appetite and weight gain. Rare problems include sleep disturbance, temperature instability, or panhypopituitarism (a deficiency in several pituitary hormones, including thyroid and growth hormone) for which replacement therapy is required.
Transventricular Endoscopic Resection/Disconnection
Transventricular Endoscopic Resection or disconnection has proven to be a good treatment option for smaller HHs ideally attached to only one wall of the third ventricle. In some cases, the HH is easily distinguished from the surrounding hypothalamus as a mass projecting into the third ventricle and light brown in color. The center of the HH is removed and where possible, the interface with the hypothalamus is carefully separated. Some surgeons believe that completely disconnecting the HH from the surrounding tissue is equally as effective as surgery with complete resection or removal of the HH tissue.
Seizure freedom outcome has been similar to the transcallosal approach and significant improvement in behavior has also been reported. Compared to the transcallosal approach, endoscopic resection usually results in a shorter hospital stay. Surgical complications are similar to the transcallosal approach.
Until the relatively recent introduction of the Transcallosal and Endoscopic approaches, resective surgery for HH was most often performed with a surgical approach from below. This approach is known as the orbitozygomatic or pterional approach. Today, with the introduction of the pathway from above, the orbitozygomatic approach is usually restricted to pedunculated HH lesions that hang down below the floor of the third ventricle. The advantage of approaching pedunculated HH lesions from below includes a shorter distance to the HH. Pedunculated HHs typically have a narrow base of attachment, and the approach from below allows the surgeon a direct view of the lesion. For large lesions that have a base in the third ventricle but may also have a component that hangs down below the third ventricle, a combination of approaches may be required for complete resection.
Gamma Knife Surgery (GKS)
Stereotactic radiosurgery is a neurosurgical procedure in which high-dose radiation is targeted at the HH tumor from multiple directions, resulting in minimal radiation exposure to normal surrounding tissue. It is noninvasive (performed without opening the skull) and there is no pain or sensation from the treatment (with the exception of discomfort from the placement of a stereotactic guidance frame on the head).
Gamma Knife Surgery (GKS) has been used worldwide for other brain tumors and abnormalities and the side effects of radiosurgery are believed to be rare, transient, and in most cases very predictable. GKS is usually considered as an option for small, deeply seated lesions where there is an increased risk of complications or functional worsening with the more invasive resective surgeries. In these types of cases, GKS is a good first option in terms of safety, effectiveness and also cost (important to many insurance companies).
Many medical centers using Gamma Knife focus treatments on the top and sides of the hamartoma. In order to maximize effectiveness and minimize risk to the optic nerves, treatment centers will often treat the critical upper portion of the hamartoma with the higher dose while limiting the dose as it gets closer to the lower portion, closer to the optic nerve. Studies have shown that treatments with less than 17-18 Gy have been less effective overall. Individuals who have shown improvement after Gamma Knife treatment have usually received a dose of 17-18 gray (Gy) to the edge of the hamartomas. To minimize risk of vision loss when the bottom of the hamartoma is near the optic nerves, the radiation level in this area may be limited to 12 Gy.
The advantages associated with GKS include avoiding the risks associated with surgical resection, including short-term memory problems, hypothalamic dysfunction, and bleeding. However, a disadvantage of radiosurgery is its delayed onset of action. It is not uncommon to wait 6 months to 18 months (for some, even up to 3 years) to realize the full effects of the treatment. For some individuals, repeat radiation may be required to get the desired effects. If GKS proves unsuccessful, standard surgery may still be an option. For a list of questions to ask your surgeon if you are contemplating GKS surgery, click here.
MRI-guided Laser Thermal Ablation
Any patient with medically refractory epilepsy and MRI-visible lesions like an HH, are potential candidates for laser thermal ablation therapy. Laser ablation is performed through a small ‘nick’ scalp incision and hole in the skull as opposed to an extensive scalp incisions and large cranial opening that is typical of standard epilepsy surgery. The treatment time and recovery time are both dramatically faster. In the event that the procedure incompletely treats a patient’s epilepsy, repeat treatments are usually straightforward and well- tolerated. Although thermal ablation is a minimally invasive surgery, there are risks. Treatment success is completely dependent on accurate placement of the laser fiber into the target lesion. Inaccurate placement of the laser is a potential risk and therefore injury to fragile or sensitive structures nearby is possible. For that reason, the majority of the treatment time is meant to ensure the accuracy of laser placement prior to initiating ablation. As with any brain procedure, there are risks of bleeding and infection, but these are always proportional to the size of the surgical exposure, treatment time and depth of treatment, all of which are lessened with laser therapy compared to open cranial surgery. The actual laser ablation treatment time is on the order of minutes. Set-up time and laser fiber placement can be 3-4 hours. The majority of patients spend one night in the hospital and are discharged the following day.
Other alternative treatment options
Several other HH treatments including stereotactic radiofrequency thermoablation, interstitial radiosurgery, vagus nerve stimulation, and ketogenic diet are discussed below.
Stereotactic Radiofrequency Thermoablation
Stereotactic radiofrequency thermoablation has been used as part of a treatment plan in a relatively small number of patients. This technique involves placement of a depth wire into the HH and physically heating the tip causing destruction to the surrounding HH tissue. Currently there have only been a few cases reported but the results appear promising. Long-term results, however, are not well documented.
Interstitial radiosurgery involves the temporary placement of radioactive seeds into the HH tissue. These radioactive seeds emit gamma radiation with minimal delivery of harmful radiation to normal surrounding structures. As with stereotactic thermoablation, placement of the seeds requires instrumentation into the brain, so the associated risks are still a factor to consider. As with stereotactic radiofrequency thermoablation, the published results of these treatments are limited. Some patients have needed to undergo seed re-implantation in order to achieve the desired results.
Vagus Nerve Stimulation (VNS) and Ketogenic Diet
Vagus Nerve Stimulation and the Ketogenic diet have been suggested as interventions for treating HH. However, there is insufficient evidence about whether they work. In a limited number of reported cases involving VNS, most did not have much success with reducing the overall number of seizures; however, some success was reported when it came to improving rage and autistic type behaviors. The data is even less clear when it comes to the ketogenic diet and its success rate for controlling either HH related seizure activity or behavior.