Ultra-Early Gamma Knife Stereotactic Radiosurgery for TN

Background Trigeminal neuralgia (TN) is a chronic, often debilitating, neuropathic facial pain condition with an approximate global incidence of 12 cases per 100,000 and a female predominance of 3:2, occurring predominantly in the sixth decade of life and increases with age, peaking around 70 years. According to the International Classification of Headache Disorders (ICHD-3), TN is characterized by "recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve (cranial nerve five - CNV) and triggered by innocuous stimuli". The CNV divides into three distinct subdivisions that carry sensory information from the scalp, forehead, eyes, upper and lower eyelids, mucous membranes of the nasal and oral cavities, frontal sinus, cheeks, teeth, lower and upper lips, and deep structures within the head. The severe lancinating pain of TN may be triggered by common somatosensory stimuli experienced in everyday life, such as chewing, speaking, brushing teeth, temperature changes, or tactile pressure to the face; pain attacks may also occur entirely spontaneously.

Given the severity of this condition, prompt pain management is critically important. Generally, pharmaceutical therapy is employed as the first-line treatment, usually in the form of antiepileptic drugs which are known to be effective against neuropathic pain, with carbamazepine (CBZ) being the gold standard. Unfortunately, these agents pose a significant risk of adverse effects ranging from ataxia, double vision, hyponatremia, confusion, and tremor, to more severe complications such as cardiac arrhythmia, aplastic anemia, hepatotoxicity, toxic epidermal necrolysis, and dosages reaching toxic levels. Frequently, increased doses are required to maintain therapeutic pain relief over time. Indeed, while pharmaceuticals may be the standard first-line treatment for TN, \>50% of patients eventually fail medical therapy. The combination of unfavourable adverse effects and diminished drug response can lead to prolonged disruption of overall well-being in a considerable proportion of patients with TN.

In general, surgical options (i.e., microvascular decompression (MVD), percutaneous rhizotomy (PR), and Gamma Knife stereotactic radiosurgery (GK-SRS)) are reserved for patients who are classified as "medically refractory". In essence, surgical treatment is offered as a rescue therapy when pharmaceutical management has failed. Of the surgical options, GK-SRS is a highly precise type of radiation therapy which is by far the least invasive, carrying with it the lowest risk of serious adverse surgery-related risks. There is good evidence to support the safety and efficacy of GK-SRS in medically-refractory TN, with some data suggesting that earlier intervention (within 3-4 years of pain onset) may result in better long-term pain outcomes. However, what is not known is whether ultra-early intervention with GK-SRS-before the actual development of medical-refractoriness-could somehow alter the natural progression of TN, thereby avoiding the need for high-dose medical therapy altogether and the side effects associated with it.

Objective

The investigators aim to evaluate the feasibility and potential benefit of GK-SRS as an ultra-early treatment option for TN. Given the well-established tolerability of GK-SRS, it is hypothesized that ultra-early GK-SRS will:

1. provide more durable pain relief compared to later GK-SRS; 2. reduce or eliminate the need for high-dose medical therapy; and 3. have a lower risk of serious complications compared to other first-line treatments.

Treatment Given the overlap between the pain of TN and other craniofacial pain entities, treatment is often delayed due to misdiagnosis. Indeed, TN patients frequently undergo unnecessary dental procedures, given the predominant localization of symptoms within the maxillary and mandibular facial dermatomes, before a correct diagnosis is made. In addition, patients presenting to primary care or emergency medical physicians with persistent and debilitating pain may be erroneously prescribed analgesics-such as opioids-which are ineffective in suppressing neuropathic TN pain.

Early recognition of TN is imperative in mitigating prolonged suffering and the potentially disabling repercussions of untreated pain. It has been shown that duration of disease may play an important role in treatment refractoriness, which argues in favour of early intervention. As mentioned above, typically medical therapy with pharmacological agents is trialled as the initial pain management strategy; in the case of intolerability or the development of medical refractoriness, surgical options are then explored as the next step.

Medical Therapy Carbamazepine and Oxcarbazepine The general recommendation for first-line TN treatment is a trial of carbamazepine (CBZ), an antiepileptic medication used for its analgesic properties. CBZ specifically targets voltage-gated sodium channels by altering sodium availability during synaptic impulses, reducing or inhibiting neuronal excitability, which serves to reduce repetitive neuropathic pain signalling.

In its earliest clinical utilization for TN, CBZ produced promising results in a small cohort of patients. A subsequent study conducted by Blom, reported that 90% of patients had a favourable initial response (within 24 hours) to CBZ. Ensuing controlled studies further confirmed the utility of CBZ in initial pain management, and CBZ became a mainstay of TN treatment.

CBZ remains the benchmark first-line treatment for TN due to its robust initial efficacy. However, a systematic review examining the efficacy and safety of CBZ in acute and chronic pain conditions revealed that 40%-66% of patients endured adverse effects. Commonly reported adverse effects of CBZ include somnolence, dizziness, double vision, rash, nausea, headache, vomiting, tremor, ataxia, disturbed sleep, mood changes, lack of concentration, memory loss, and hyponatremia. In rare circumstances, severe adverse effects may be experienced, including myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, elevated liver enzymes, hematologic dyscrasias, thrombocytopenia, and aplastic anaemia. It is generally recommended that those with medical histories of cardiac, liver, bone marrow, or renal disease undergo regular blood monitoring, as CBZ may be more likely to produce toxic effects in these patients. In addition, the presence of the HLA-B\*15:02 allele found almost exclusively in Asian genealogy warrants genetic testing for patients with Asian lineage to determine their potential risk of CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis that may have life-threatening implications.

In the case of CBZ intolerance, oxcarbazepine (OXC), a keto derivative of CBZ, may be trialled, as the mechanism of action parallels carbamazepine; however, OXC has been shown to have fewer side effects, contraindications, and overall better tolerability. Similar to CBZ, common adverse effects include sedation, dizziness, poor concentration, diplopia, nausea, headache, somnolence, ataxia, and thrombocytopenia, typically experienced to a lesser degree compared to CBZ. Of note, the incidence of hyponatremia is dose-dependent and of particular concern, so the use of OXC should be monitored carefully to avoid electrolyte imbalance.

A large retrospective study examining the natural history of classical TN with focus on drug responsiveness and tolerability of CBZ and OXC demonstrated robust initial responsiveness ranging between 98% (CBZ) and 94% (OXC). However, following mean periods of approximately 8.6 (CBZ) and 13 (OXC) months, a significant proportion of patients (27% CBZ and 18% OXC) developed intolerability and required subsequent dosage reduction to inadequate levels for appropriate pain management. CNS disturbances, including somnolence, postural unbalance, and dizziness, were the most prominent causes of treatment discontinuation in patients treated with CBZ, while somnolence, postural unbalance, and hyponatremia were the primary causes for discontinuation of OXC.

In addition, a quantitative examination of the frequency of adverse effects and overall tolerability in patients receiving CBZ and OXC for the treatment management of neuralgiform pain conducted by Besi et al. found that dosage increases sufficient for pain management subsequently increased adverse cognitive effects (i.e., memory and concentration disturbances). More specifically, they found that a standard one-unit dosage increase resulted in a 50% increase in the likelihood of worsening side effects and eventual incapacity to reach therapeutic dosage requirements for adequate pain suppression. Of note, a review by Taylor et al. analyzing the treatment of CBZ for classical TN over a sixteen-year period found a significant drop in efficacy by year four with an overall 44% failure rate, requiring alternative treatment.

Alternatives to CBZ and OXC Gabapentin The efficacy of gabapentin for the treatment of TN has not been clearly demonstrated. However, clinical experience shows better tolerability over CBZ or OXC, albeit with lower efficacy. Gabapentin is still associated with somnolence, dizziness, headache, confusion, nausea, and hyperlipidemia. Nevertheless, gabapentin may be used for patients who are intolerant to or for whom CBZ or OXC are ineffective.

A recent two-year, real-life prospective study by Heinskou et al. aimed at evaluating the prognosis of medically-treated TN in a highly structured multidisciplinary management program. The most frequently utilized drugs at the start of the study were OXC (29%), CBZ (28%), and gabapentin (28%). During the two-year follow-up period, however, 60% of patients experienced a change in the prescribed type or number of medications, and treatment discontinuation occurred in 23% of patients. Although a tightly regulated, individualized drug treatment regimen resulted in a favourable prognosis for nearly half of the patients analyzed at the two-year mark, 45% of patients initially enrolled in the study were lost to follow-up, and a significant number of patients (32%) reported a poor outcome (no pain reduction in 23% or a worsening of pain in 9%). Moreover, a large subset of patients (27%) were referred to surgery due to refractoriness or intolerability, though the optimal time for referral to surgery remains an important unanswered question. The authors do suggest that optimization of treatment "should be done before patients are considered medically refractory".

Despite the favourable tolerability of OXC, a long-term cohort study comparing OXC and surgical management of intractable TN found that effectiveness was short-term, subsequently necessitating surgical intervention as a rescue therapy. Referral to a neurosurgeon varied between 3 months to 11 years following initiation of medical therapy. Surgery was associated with a better outcome than OXC and the authors concluded that patients can benefit substantially from having surgery earlier in the disease process.

In summary, there is a high likelihood (\>50%) that, over time, TN patients initially responsive to medical therapy will become medically refractory, failing to respond to alterations in medication type or dosage increases. Ultimately, as outlined above, a consequence of medical therapy is the marked probability of developing intolerance resulting from dosage requirements exceeding safe levels, significantly limiting its use. The long-term efficacy of medical therapy is compromised by intolerability, and over time, intractability of pain.

Surgery has historically been indicated for those who become intolerant or resistant to the ever-increasing dosage requirements required to sustain the efficacy of medical therapy. However, there is no consensus as to the number of failed medical treatments necessary to ren

• Secondary outcome measure - treatment-related adverse events [Срок оценки: At 6, 12, 24 months, and 5 years after the day of GK-SRS treatment, for participants in the Experimental Arm. At 6, 12, 24 months, and 5 years after enrolment, for participants in the No-intervention Arm]
• Secondary outcome measure - medication [Срок оценки: Experimental Arm: Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. No-intervention Arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment]
• Secondary outcome measure - complete pain relief [Срок оценки: 2 years after the day of GK-SRS treatment]
• Secondary Outcome Measure - long term satisfactory pain relief [Срок оценки: 5 years after day of GK-SRS treatment]
• Secondary Outcome Measure - facial numbness [Срок оценки: At 6, 12, 24 months, and 5 years after GK-SRS treatment]
• Secondary outcome measure - crossover [Срок оценки: At 6, 12, 24 months, and 5 years after enrolment]
• Secondary outcome measure - repeat surgical referral [Срок оценки: At 6, 12, 24 months, and 5 years after GK-SRS treatment]