Radiation therapy in the Treatment of Neurological Disorders

Radiation therapy has been widely adopted in the treatment of various neurological disorders, for different aims such as pain relief, control of the symptoms, and obliteration of brain arteriovenous malformations. Moreover, RT is a non-invasive approach that can be safely adopted also in elderly patients.

radiotherapy
non-malignant disorders
non-oncological radiotherapy

1. Epilepsy

A total of 0.5% of the world’s population suffers from epilepsy. About 30–40% of the patients do not benefit from pharmacological therapy and are eligible for surgical treatment. In patients where the pharmacological and surgical alternatives have been exhausted, RT is an option. RT, compared to surgery, has the advantage of not being invasive with low risk of neurological damage to the patient. Rauch C. et al. [60] reported first-time long-term outcome (median 10 years) of fractionated stereotactic radiotherapy (FSRT) in 11 patients with drug-resistant epilepsy. The biologically equivalent dose ranged from 26.3 to 58.3 Gy (α/β = 10). None of the patients developed temporary or permanent neurological deficits. Treatment resulted in improvement of seizure frequency in seven patients: five of them had a decrease in seizure frequency, and two of them were seizure-free at last follow-up.

Liang S et al. [61] reported the long-term outcome of seven patients with temporal lobe epilepsy (TLE) treated with very low-dose LINAC based FSRT, treated with marginal dose of 12 Gy at the 85% isodose line. Reduction of seizure frequency post-FSRT was 50% in two cases, 30% in one case, and 0% in two cases, and seizure frequency increased more than 100% in two cases. No patient was seizure free at the last follow up. Two cases presented transitory complications and two cases showed an obvious drop in IQ, memory decline, and permanent neurologic complications, including partial aphasia and mild hemiplegia in one case, and progressive ataxia and cognition decline in another case. Bartolomei F et al. [62] reported outcome of 15 patients with TLE with median follow-up of 8 years (range 6–10 years) treated with gamma-knife with a marginal dose of 24 Gy. At the last follow-up, 9 of 16 patients (60%) were considered seizure free. A total of 60% of the patients experienced mild headache and were placed on corticosteroid treatment for a short period. All patients who were initially seizure free experienced a relapse of isolated aura (10/15, 66%) or complex partial seizures (10/15, 66%) during antiepileptic drug tapering. Restoration of treatment resulted in good control of seizures. Results are maintained over time with no additional side effects. Long-term results are comparable with conventional surgery.

Barbaro et al. [63] evaluated the effectiveness of radiosurgery, at the level of the amygdala, hippocampus, and parahippocampal gyrus as an alternative to surgery. Thirteen high-dose (24 Gy) and seventeen low-dose (20 Gy) patients were treated. Both groups showed significant reductions in seizures within a year of treatment, without observing major safety issues with high-dose stereotactic radiosurgery (SRS) versus low-dose SRS.

On these bases, radiotherapy has the potential to control the frequency and intensity of seizures in patients with pharmacoresistant epilepsy with mild long-term side effects if administered with proper fractionation, dose prescription, and target volume definition.

2. Trigeminal Neuralgia

Trigeminal neuralgia (TN) is a neurological disease that cause intense facial pain, usually paroxysmal and excruciating, due to an alteration of the V cranial nerve (predominantly the mandibular and maxillary branches). In patients with medications failure/significant adverse events, radiotherapy (SRT, mainly SRS) may be an important therapeutic option. For SRS Gamma-Knife, linear accelerators and Cyber-Knife can be used. The three techniques showed no differences in terms of pain control, whereas the time to recurrence ranged from 6 to 48 months [78].

Smith et al. [64] performed a retrospective study that evaluated cohort of 169 patients treated with LIANC-SRS. The authors investigated different doses and volumes, concluding that increased dose and volume of brainstem irradiation improve clinical outcomes. Similarly, Rashid et al. [65] evaluated 55 patients with TN and treated with LINAC SRS up to a total dose of 90 Gy with 20% isodose line constraint to brainstem. After 30 months median follow-up, 69% of patients were pain free. Another important study has reported the outcomes of using Cyber-Knife SRS administered to 527 patients [66]. Dose prescription was 60–65 Gy to the 80–90% isodose line. A brainstem volume equal to or less than 1 cm³ was exposed at a dose of 10 Gy, with a maximum point dose (0.035 cm³) of 30% of the prescription dose. The pain relief rates were 87%, 82%, and 76% at 12, 24, and 36 months, respectively.

Lovo EE et al. [67] reported the outcome of 14 patients with TN treated with SRS to the Centromedian and Parafascicular Complex of the contralateral thalamus. They used a gamma angle regularly fixed at 90° and using a 4 mm collimator and the prescribed dose was 140 Gy to Dmax. Almost all patients (90%) reported some form of relief. Six patients (60%) reached the threshold of 50% pain relief. For four patients (40%), the procedure failed because the pain never improved.

Kundu B et al. [68] recently performed a retrospectively evaluation of patients with TN undergoing LINAC-SRS. The patients were evaluated with Barrow Neurological Institute (BNI) pain score and after a median follow-up of 5 months, 72% of the patients showed an improvement in this pain evaluation.

A retrospective study by Fraioli et al. of 45 patients compared SRS to FSRT using a linear accelerator. The authors compared 40 Gy in a single fraction and 72 Gy in six fractions. Patients treated with FSRT showed a higher pain recurrence rate than SRS (27.3% versus 8.3%) [79].

Finally, reirradiation with SRS can still be used in case of recurrence, with a pain relief rate of 50% as showed in two retrospective studies [80,81]. The reirradiation was usually delivered between 15.7 and 26.1 months after the first irradiation, with a dose in the range 70–80 Gy.

3. Brain Arteriovenous Malformations

Brain arteriovenous malformations (AVMs) are the persistence of a direct link between an artery and a vein; the nidus is located where small arteries and veins are connected [82]. Brain AVMs are rare (incidence estimated between 1.12 and 1.42 cases per 100,000 person-years) and mostly occur in young patients [83].

AVMs may be found as an incidental finding. They may be associated with intracranial hemorrhage, seizures, headaches, and/or neurological deficits. CT and MRI angiography are useful for the accurate diagnosis and nidus definition. Treatment approaches for AVMs are neurosurgery, embolization, and intracranial SRS. Stereotactic radiosurgery has a clinical obliteration rate of 60–80% [69,70,71,72]. The clinical benefit of SRS induced obliteration appear after 3 years or more. The success rate was increased with smaller volume (up to 30 cm³), lower Spetzler-Martin grade, higher dose, and steeper dose gradient. Embolization performed before SRS provided significantly lower obliteration rates than SRS alone (at 3 years: 41% versus 59%, respectively; p < 0.00001) [84,85]. Some AVM locations (functional areas, as thalamus) are related to poorer outcomes and require multimodal management [86]. Fractionated intracranial SBRT is poorly used in patients with AVM, mainly due to the low obliteration and morbidity rates initially reported [87]. Most recent results had an obliteration rate of 50% using fractionated intracranial SBRT delivering equivalent 2 Gy fraction doses higher than 70 Gy [88]. Symptomatic and permanent radiation-induced side effects have been described in 8 to 11% and in 1 to 4% of patients treated with SRS, respectively [71]. Stereotactic radiosurgery can be repeated when no complete obliteration is reported after the initial treatment. This is likely to occur in patients with AVMs larger than 10 cm³ and/or with high Spetzler-Martin grade [71]. Overall, the risks of hemorrhage and radionecrosis have to be considered and the treatment decision needs to be taken in a multidisciplinary setting in which the situation of each patient is assessed individually.

4. Graves Ophthalmopathy

Graves ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves’ disease. Although GO is severe in only 3–5% of affected individuals, quality of life is severely impaired even in patients with mild GO. RT is a well-established method of treatment for GO. The main rationale is its anti-inflammatory effect and the high radiosensitivity of T lymphocytes and orbital fibroblasts. Although there are several reports about the benefits of RT [73,74,75], optimal initial treatment and its combination with steroids is still controversial. Various RT regimens with different doses and fractionations have been used: 16 or 20 Gy delivered in 8–10 fx (five days/week) is usually considered the standard [89]. A consensus statement from the European Group on Graves’ Orbitopathy does not recommend doses higher than 20 Gy [90]. Recent studies evaluated altered fractionation RT for GO. In a randomized study, Kahaly et al. [76] compared the efficacy and tolerability of three RT regimens of 1 Gy given weekly for 20 weeks for a total dose of 20 Gy; 1 Gy given daily for 2 weeks for a total dose of 10 Gy; and 2 Gy given daily for 2 weeks for a total dose of 20 Gy for patients with moderately severe GO. The authors concluded that whereas all regimens provided similar response rates, the protracted regimen had a better effectiveness and tolerance. Cordoso et al. [77] demonstrated the efficacy of orbital RT with a total dose of 10 Gy, fractionated in 1 Gy once a week over 10 weeks in 18 patients with GO.

Overall, favorable responses have been reported in 60% of cases. The best responses were noted for inflammatory signs and recent onset of extraocular muscle involvement. RT is well tolerated and safe and a careful selection of patients is necessary.

This entry is adapted from the peer-reviewed paper 10.3390/jpm12101677

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