Corpus callosotomy: anterior two-thirds (two-stage) versus complete (one-stage)

Introduction

Corpus callosotomy (CC) is a palliative surgical disconnection to treat drug resistant epilepsy (DRE) characterized by tonic or atonic drop attacks, generalized seizures or partial seizures with secondary generalization. The highest reported efficacy is for atonic or drop seizures, and complete callosotomy is more effective in controlling seizures compared to partial or anterior 2/3 callosotomy but is associated with a higher risk of disconnection syndrome. Partial callosotomy should be reserved for highly functional individuals with mild to moderate seizure burden, and patients older than 10 years of age. Two stage surgery is useful when concerns of disconnection syndrome or postoperative neurologic recovery predominate, and an initial anterior 2/3 callostomy is not effective. While CC is traditionally performed through an open craniotomy and microsurgical disconnection via an interhemispheric approach , more recently stereotactic laser ablation [MRI guided laser interstitial thermal therapy (LITT)] has been used to perform CC as a minimally invasive surgical option .

Surgical indications

CC is a palliative surgical procedure primarily used to treat generalized DRE. It is most effective in the management of tonic or atonic “drop” seizures, most commonly in the context of Lennox–Gastaut syndrome (LGS). Other types of generalized seizures and focal seizures with secondary generalization may also be remediated by CC , however the clinical response is more variable. In principle, transecting the fibers of the corpus callosum interrupts the largest structural pathway between both hemispheres and halts the electrical spread of seizures . Anterior 2/3 or partial CC and complete CC are commonly performed; while partial CC is less effective at controlling seizures, complete CC carries a risk of disconnection syndrome. When to offer partial callosotomy versus complete callosotomy remains controversial, as disconnection syndromes are difficult to predict and the incidence is unclear. However, in patients with higher levels of neurological function and lower seizure burden, it is common to offer partial CC as an initial surgical strategy, proceeding to a complete CC in a staged approach only if partial CC is ineffective at seizure control.

As a palliative surgical procedure, seizure freedom after CC is rare . Other palliative surgical options include neuromodulation, primarily vagal nerve stimulation (VNS). VNS is a less invasive surgical option and is sometimes offered before CC due to significantly less surgical risk. However, VNS may be less effective compared to CC, especially for atonic seizures. When counseling patients and families about the surgical options of CC versus VNS, emphasis should be placed on the risks of surgery, treatment efficacy, and quality of life. VNS may also be performed after partial or complete CC as an additional palliative measure . More recently, corticothalamic responsive neurostimulation (RNS) has been used as a potential therapeutic option for patients with LGS, and it is being investigated in clinical trials (NCT05339126). More advanced neuromodulation strategies in patients with LGS and generalized DRE, including RNS, may represent an important future direction .

Surgical outcomes

Partial versus complete callosotomy

A careful balance must be struck preoperatively when deciding between a partial (anterior 2/3) versus complete callosotomy. Complete CC clearly provides superior seizure reduction: a metaanalysis in pediatric patients demonstrated complete CC resulted in a significantly higher rate of worthwhile seizure reduction compared to partial CC (88.2% vs 58.6%, p =0.049). Further, complete CC provided a 77.8% meaningful reduction in atonic seizures, compared to 45.4% for partial CC ( p =0.00036) . In a metaanalysis of 1742 adult and pediatric patients who underwent open CC, complete seizure freedom was reported as 18.8% and freedom from atonic seizures was reported as 55.3%. The presence of infantile spasms (OR 3.86), normal MRI findings (OR 4.63), and epilepsy duration <15 years (OR 2.57) were associated with a higher incidence of seizure freedom postoperatively. Atonic seizure resolution was predicted by complete rather than partial callosotomy (OR 2.90) and idiopathic etiology of epilepsy (OR 2.84).

Smyth and colleagues demonstrated that 91% of patients undergoing complete CC achieved meaningful seizure control as opposed to 75% for partial CC . Kasabeh et al. shared similarly improved results for complete CC versus partial CC. In their analysis, no other preoperative variables were associated with good surgical outcomes . Shim et al. show meaningful improvement in overall seizure profile in 76.4% and meaningful improvement in atonic seizures in 91.2% with complete CC . Relapse was lower in the complete CC group as compared to the partial callostomy group (7% versus 31%) . The majority of parents of complete CC patients reported improved daily function and postoperative satisfaction with the procedure .

In addition, a higher rate of failure to improve after partial CC requiring staged completion has been observed in younger patients . Kasasbeh and colleagues reported a significantly higher rate of initial complete CC in younger patients in a retrospective single center analysis . Alternately, patients who underwent staged complete CC were more likely to undergo initial partial CC at a younger age compared to patients who underwent anterior 2/3 callosotomy alone ( p =0.02) . Shim et al. also endorse improved postoperative function and parental satisfaction in younger patients undergoing complete CC. Conversely, however, they caution against poor results of complete CC in patients <3 years of age but this has not been investigated elsewhere in the literature .

While this literature is compelling, others emphasize that there is a subset of patients for whom partial CC is sufficient for good seizure outcomes , and recommend a staged surgical approach, with completion of the CC in patients who do not respond to partial CC.

Disconnection syndrome

The opportunity for optimal seizure outcome must be balanced with the risk of disconnection syndrome. Postoperative disconnection syndrome may occur with either complete or partial CC and is characterized by mutism, apraxia, weakness, aphasia, dysgraphia and/or agnosia. Split-brain syndrome may produce curious and disabling phenomena including the inability to process visual stimuli presented to a unilateral visual hemifield. Similar difficulties may be experienced with dichotic listening tasks. In addition, performing tasks which require bimanual coordination may be extremely challenging. Disconnection syndrome, although somewhat infrequent, can be functionally disabling to the patient despite good seizure control.

Strong evidence predicting disconnection syndrome after CC is lacking , however, evidence suggests the risk may be higher with complete CC. A recent metaanalysis of open CC in 1742 adults and children did not demonstrate a significantly higher rate of disconnection syndrome associated with complete CC (8.0%) versus partial CC (12.4%) . Shim et al. report no cases of disconnection syndrome with complete CC in their series . A metaanalysis of 377 pediatric patients demonstrated a 12.5% transient disconnection syndrome in complete callosotomy, compared to no observed cases with a partial callosotomy. The disconnection syndrome was noted to be “subtle” and resolved within 6 weeks in each reported case. In all but one case, the disconnection syndrome occurred in children with LGS or severe intellectual disability .

Younger age at surgery (<10 years of age or before puberty) may be associated with a lower risk of disconnection syndrome . It is hypothesized that younger patients exhibit “callosal plasticity” and can recover changes to visual processing . It is also debated whether the splenium is responsible for the interhemispheric communication and processing of visual information . The impetus to perform a partial CC is presupposed on the notion that the splenium is critical in visuo- and tactuomotor processing; however disconnection syndrome may still observed after partial CC in some patients .

Other neurologic complications

Overall rates of adverse events after open CC in small, individual series are noted between 8.1% to 12.4% with transient neurological deficit being the most common . Comparing operative risk when performed via open craniotomy, complete CC was associated with 30 minutes of additional operative time compared to partial CC, without any other significant differences, including blood loss or length of hospitalization . Some studies have demonstrated an overall higher rate of postoperative neurological deficit with complete CC. One study demonstrated new postoperative neurologic deficits in 15.4% of patients after complete CC, compared to 6.9% following anterior 2/3 CC . In the same study, minor surgical complications (hematoma, subdural hygroma, venous embolism and infection) were similar between the two groups, occurring in 2.7% of complete CC cases compared to 5.9% of anterior 2/3 CC patients . Other single center pediatric series have found no significant differences in surgical complications seen between techniques . Published data on outcomes, disconnection syndrome and other complications are improved by pooling through metaanalyses but are still limited by the small and retrospective nature of the original studies, patient variability and bias due to different criteria for surgical selection, variability in surgical technique, and variable definitions of complete and partial CC between studies .

One stage versus two stage surgery

Considerable debate exists surrounding single versus staged surgical intervention for CC. As discussed above, the current literature is more supportive of single stage complete CC as a first line option for acceptable patients due to improved seizure outcomes including a higher likelihood of improving a broader spectrum of clinical seizure semiologies . A nuanced approach consists of offering single stage complete CC for younger patients, as well as patients with poor neurologic function or an extremely high seizure burden . Indications for partial CC or two stage surgery are not well defined in the literature. Broadly speaking, the general practice for partial CC with a possible second stage completion surgery is reserved for children who are high functioning, those with less severe epilepsy, or children >10 years of age . In a study comparing one versus two stage surgery, fifteen pediatric patients underwent a partial CC and seven of these went on to require a second stage completion surgery (46.7%) .

Completion of callosotomy after suboptimal results after partial callosotomy is likely to improve seizure outcomes . Improvement after second stage surgery is reported to occur between 20% to 60% of cases . This suggests that those requiring a second stage operation have more severe epilepsy. No strong data suggest a staged approach is associated with less overall morbidity than a single stage complete CC. However, some experts advocate that staged intervention reduces the potential for disconnection syndrome and may allow for sufficient neurological recovery between stages. A second stage completion CC is typically considered 6–12 months after the initial surgery if the patient continues to have drug resistant seizures that are disabling . In one study, single stage upfront complete CC was associated with better seizure outcomes than partial anterior two thirds CC or staged CC , as well as a lower likelihood of VNS placement after CC . Worsening seizures or emergence of a new seizure type postoperatively is a rare but known occurrence after CC, occurring in approximately 10% of patients . The risk may be higher in single stage complete CC but this has not been widely reported .

Laser interstitial thermal therapy versus craniotomy

LITT is a neurosurgical technique which has been applied to multiple structural pathologies including tumor, cavernoma, and epileptic lesions. Curry et al. first described MRI guided LITT for lesional epilepsy in 2012 . Similar stereotactic and ablative techniques are now being extrapolated for disconnection procedures including CC, posterior quadrant disconnection and hemispherotomy . The technique is based on the targeted delivery of heat through a laser fiber which then coagulates brain tissue in a controlled fashion guided in real time by MRI thermography . Two systems are commercially available for use at this time: Visualase (Medtronic, Inc.) and Neuroblate (Monteris, Inc.). Each platform differs in its cooling mechanism, laser pull back mechanism, laser fiber diameters and side fire versus omnidirectional ablation capabilities .

Strict indications for LITT versus open CC have not been standardized at this time . Metaanalyses in adults demonstrate noninferiority of the technique as compared to open CC. Pediatric data are too limited to definitively compare the two techniques; however, as LITT is undertaken more frequently, a better understanding of comparative efficacy, safety and complications will emerge. Initial retrospective comparison in a pediatric cohort similarly suggests noninferiority of the technique and similar seizure related outcomes . Parental/guardian hesitation regarding open surgery may center on inherent risks of an open craniotomy, comorbid medical fragility, unclear expected postsurgical benefit, or risk of disconnection syndrome . Thus, LITT may be a more palatable option for these families . From an anatomical perspective, LITT is more feasible in cases with a thick corpus callosum with a flat orientation. As expected, LITT incurs significantly less blood loss, shorter hospital stay and longer operative time compared to open techniques . The available evidence comparing seizure outcomes between LITT and CC is presented in Table 15.1 . Controversy exists regarding whether a LITT CC can truly provide a complete ablation even when this is the intended surgical goal. Caruso et al. demonstrated easily missed areas representing residual connection in the corpus callosum after a laser ablation . Inherent in the challenge of laser ablation, is attempting to perform a complete ablation of a large curved midline intracranial structure using linear trajectories.

Table 15.1

Outcomes for laser interstitial thermal therapy corpus callosotomy in pediatric epilepsy.

Study	Number of pediatric cases	Technique (partial vs complete CC)	Outcomes	Complications
Karsy et al. (April 2018)	1	Partial	Significant reduction in number and severity of seizures at 12 months	None
Palma et al. (March 2019)	2	Partial	Case 1: Reduction in seizures and resolution of drop attacks, maintained at 4 years follow up Case 3: Near resolution of seizures and complete resolution of drop attacks at 2 years	Not discussed
Badger et al. (April 2020)	1	Complete	Seizure freedom from atonic and GTC seizures at 13 mos	Transient hemiparesis
Roland et al. (January 2021)	10	Partial and complete	50% achieved Engel II or III at mean follow up of 1 year	1 hemorrhage, 1 fiber misplacement
Caruso et al. (April 2021)	8	Partial and complete	Preop 4.4 seizures and 8.1 drop attacks per day versus postop 1.34 seizures and 0.38 drop attacks per day	1 patient with venous thromboembolism attributable to Factor V deficiency and spinal fluid leak from laser fiber site
Mallela et al. (October 2021)	10	Partial and complete	71% seizure freedom from drop attacks at 3 mos (n=7)	Asymptomatic intraventricular hemorrhage ( n =1), transient disconnection syndrome ( n =4)
Best et al. (December 2022)	2	Partial and complete	Case 2 partial CC: Decrease in atonic seizures, increase in GTC frequency with decreased durationCase 3 complete: Seizure free at 18 months	Case 2 fiber misplacement, Case 3 transient SMA syndrome