Retinal tear and posterior vitreous detachment following repetitive transcranial magnetic stimulation for major depression: A case report

Repetitive transcranial magnetic stimulation (rTMS) is a well-established treatment for medically refractory major depressive disorder (MDD), using powerful, focused magnetic pulses (1.0–2.5 T) delivered through an electromagnetic coil to stimulate the dorsolateral prefrontal cortex (DLPFC) [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (220) Google Scholar]. rTMS is a safe procedure, with side-effects usually limited to scalp pain during stimulation, transient and mild headache and fatigue after stimulation, and rare seizures (<0.1%) [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (220) Google Scholar]. Although uncommon, eye symptoms such as pain or discomfort have also been reported [[2]O’Reardon J.P. Solvason H.B. Janicak P.G. Sampson S. Isenberg K.E. Nahas Z. et al.Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.Biol Psychiatry. 2007; 62: 1208-1216https://doi.org/10.1016/j.biopsych.2007.01.018Abstract Full Text Full Text PDF PubMed Scopus (1011) Google Scholar,[3]Carpenter L.L. Aaronson S.T. Clarke G.N. Holtzheimer P.E. Johnson C.W. McDonald W.M. et al.rTMS with a two-coil array: safety and efficacy for treatment resistant major depressive disorder.Brain Stimul. 2017; 10: 926-933https://doi.org/10.1016/j.brs.2017.06.003Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. The development of sight-threatening conditions are rare, with a single case in the literature reporting the development of a retinal tear following rTMS [[4]Kung S. Ahuja Y. Iezzi R. Sampson S.M. Posterior vitreous detachment and retinal tear after repetitive transcranial magnetic stimulation.Brain Stimul. 2011; 4: 218-221https://doi.org/10.1016/j.brs.2011.08.007Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. In this letter, we describe the occurrence of posterior vitreous detachment (PVD) and retinal tear in a patient receiving rTMS and provide recommendations for ocular screening and management in these cases. A 50-year-old female patient with a 6-year history of medically refractory MDD was referred for rTMS. Medication history included 5 unsuccessful trials of antidepressant medication at optimal dosage and of adequate duration, as well as psychotherapy. Past medical and ophthalmological history were unremarkable, with no rTMS contraindications. The patient underwent daily rTMS sessions of bilateral theta burst stimulation (TBS), consisting of continuous TBS (cTBS) stimulation over the right DLPFC (triplet 50 Hz bursts, 5 per second, 600 pulses, 40 seconds total) followed by intermittent TBS (iTBS) stimulation over the left DLPFC (600 pulses per session, 2s on and 8s off, 3 m 9 s total). Treatment was delivered using a MagPro R30 device with a Cool-B70 coil (MagVenture, Farum, Denmark) using the adjusted BeamF3/F4 algorithm for targeting [[5]Mir-Moghtadaei A. Caballero R. Fried P. Fox M.D. Lee K. Giacobbe P. et al.Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.Brain Stimul. 2015; 8: 965-973https://doi.org/10.1016/j.brs.2015.05.008Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Treatment was administered at 120% of resting motor threshold (rMT), which was 54% of maximum stimulator output on the right side and 48% on the left side. During treatment, the reported pain on the verbal rating scale (VRS) averaged 8 out of 10 (VRS scale 0–10, 10 = maximum tolerable pain). The initial course was planned for 30 sessions, but the patient reported increased ocular pain, floaters and a supero-temporal shadow in her left eye following the 25th session; treatment was discontinued, and the patient referred to the ophthalmology team. On examination, her best corrected visual acuity was 20/20 in both eyes (OU) and she had an unremarkable slit-lamp exam. On fundus exam, the left eye (OS) presented with a mild vitreous hemorrhage, PVD, and a large horseshoe retinal tear (HST) at 6 o’clock adjacent to an area of lattice degeneration with an attached retina. The right eye had no significant fundus findings. The patient had an unremarkable past ocular history, except for myopia (−2.00 diopters OU). She had been seen by her optometrist for a routine follow-up 15 months prior, and fundus photos revealed absence of retinal tears. She promptly underwent laser retinopexy to the HST and lattice degeneration OS. The patient was re-assessed by the ophthalmologist one month later and her retinal exam was stable with no new retinal tears and good laser retinopexy scars (Fig. 1). The vitreous is a clear matrix composed of collagen fibrils, hyaluronic acid and of 99% water located between the lens and the retina [[6]American Academy of Ophthalmolgy - the Eye M.D. AssociationRetina and Vitreous, Basic and Clinical Science Course Section. 12. American Academy of Ophthalmolgy, Singapore2011Google Scholar]. Enzymatic and nonenzymatic processes, and a reduction in the network density of collagen fibrils may lead to vitreous liquefaction and shrinkage of the gel, which ultimately results in separation of the vitreous from the retina. This phenomenon referred to as a PVD is typically an age-related process, usually occurring in patients over the age of 50 years. However, certain risk factors, including trauma, can result in an earlier development of PVD. The most frequent symptoms related with acute PVD are floaters and photopsias [[6]American Academy of Ophthalmolgy - the Eye M.D. AssociationRetina and Vitreous, Basic and Clinical Science Course Section. 12. American Academy of Ophthalmolgy, Singapore2011Google Scholar,[7]Gishti O. van den Nieuwenhof R. Verhoekx J. van Overdam K. Symptoms related to posterior vitreous detachment and the risk of developing retinal tears: a systematic review.Acta Ophthalmol. 2019; 97: 347-352https://doi.org/10.1111/aos.14012Crossref PubMed Scopus (11) Google Scholar]. During the evolution of a PVD, the vitreous may cause traction on certain areas of the retina, which can result in a retinal tear [[7]Gishti O. van den Nieuwenhof R. Verhoekx J. van Overdam K. Symptoms related to posterior vitreous detachment and the risk of developing retinal tears: a systematic review.Acta Ophthalmol. 2019; 97: 347-352https://doi.org/10.1111/aos.14012Crossref PubMed Scopus (11) Google Scholar]. Symptomatic retinal tears require prompt treatment as these can lead to retinal detachments [[7]Gishti O. van den Nieuwenhof R. Verhoekx J. van Overdam K. Symptoms related to posterior vitreous detachment and the risk of developing retinal tears: a systematic review.Acta Ophthalmol. 2019; 97: 347-352https://doi.org/10.1111/aos.14012Crossref PubMed Scopus (11) Google Scholar,[8]Mastropasqua L. Carpineto P. Ciancaglini M. Falconio G. Gallenga P.E. Treatment of retinal tears and lattice degenerations in fellow eyes in high risk patients suffering retinal detachment: a prospective study.Br J Ophthalmol. 1999; 83: 1046-1049https://doi.org/10.1136/bjo.83.9.1046Crossref PubMed Scopus (49) Google Scholar]. In landmark rTMS clinical trials, eye pain was reported in 6.1% of patients either during or after sessions, but no mention of visual symptoms were made [[2]O’Reardon J.P. Solvason H.B. Janicak P.G. Sampson S. Isenberg K.E. Nahas Z. et al.Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.Biol Psychiatry. 2007; 62: 1208-1216https://doi.org/10.1016/j.biopsych.2007.01.018Abstract Full Text Full Text PDF PubMed Scopus (1011) Google Scholar,[9]George M.S. Lisanby S.H. Avery D. McDonald W.M. Durkalski V. Pavlicova M. et al.Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial.Arch Gen Psychiatr. 2010; 67: 507-516https://doi.org/10.1001/archgenpsychiatry.2010.46Crossref PubMed Scopus (606) Google Scholar]. In this patient, based on the temporal relationship between the onset of symptoms one day after an rTMS treatment, and given that these findings were not present in her recent eye exam prior to rTMS, it is possible that rTMS precipitated or accelerated the development of a PVD and a large retinal tear. The mechanism of how rTMS resulted in a retinal tear in this case is unknown, however it is most likely related to the repetitive saccades secondary to facial and ocular muscle contraction that occurs throughout multiple treatment sessions. The repetitive saccades may result in disorganization of collagen fibrils, vitreous liquefaction and, consequently, in the development of an acute PVD. Once the PVD occurs, ongoing repetitive saccades likely results in vitreous traction on the retina and a subsequent retinal tear. Consistent with this theory, other studies have suggested that repetitive saccades lead to increased tractional forces on the peripheral retina in the setting of a PVD [[10]Repetto R. Tatone A. Testa A. Colangeli E. Traction on the retina induced by saccadic eye movements in the presence of posterior vitreous detachment.Biomechanics Model Mechanobiol. 2011; 10: 191-202https://doi.org/10.1007/s10237-010-0226-6Crossref PubMed Scopus (26) Google Scholar]. Our patient had lattice degeneration, which may have increased the susceptibility of developing a retinal tear while the PVD was occurring. Also, it is important to underline the rarity of such cases in the published literature, with this report being the second one to date [[4]Kung S. Ahuja Y. Iezzi R. Sampson S.M. Posterior vitreous detachment and retinal tear after repetitive transcranial magnetic stimulation.Brain Stimul. 2011; 4: 218-221https://doi.org/10.1016/j.brs.2011.08.007Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]; this event was the first noted in >40 000 cumulative sessions for the clinic treating this patient. Patients receiving rTMS should be carefully followed and actively questioned in regard to ophthalmological symptoms such as floaters and photopsia, and the presence of these symptoms at baseline should be documented before initiating rTMS. For patients presenting with risk factors, such as history of recent ocular trauma, history of recent ocular surgery, pathologic myopia, prior retinal detachment, prior laser retinopexy treatment, family history of retinal detachment, a baseline ophthalmological examination may be warranted. All other patients should be counselled to advise their physician if they experience an increase in floaters, flashes of light, a visual field defect or a reduction in central vision during or after the initiation of rTMS therapy. If new symptoms occur while a patient is under treatment, rTMS should be withheld pending ophthalmological examination [[7]Gishti O. van den Nieuwenhof R. Verhoekx J. van Overdam K. Symptoms related to posterior vitreous detachment and the risk of developing retinal tears: a systematic review.Acta Ophthalmol. 2019; 97: 347-352https://doi.org/10.1111/aos.14012Crossref PubMed Scopus (11) Google Scholar]. In the event that the patient develops a retinal tear or retinal detachment attributed to rTMS, it may be advisable to discontinue future treatment. SBM reports no conflicts of interest. JPM reports research grants from the Brain & Behavior Research Foundation NARSAD Young Investigator Award and salary support for his graduate studies from the Branch Out Neurological Foundation. VJ and NF report no conflicts of interest. JD reports research grants from CIHR , the National Institute of Mental Health , Brain Canada , the Canadian Biomarker Integration Network in Depression , the Ontario Brain Institute , the Weston Foundation , the Klarman Family Foundation , the Arrell Family Foundation , and the Buchan Family Foundation , travel stipends from Lundbeck and ANT Neuro, in-kind equipment support for investigator-initiated trials from MagVenture, and is an advisor for BrainCheck, TMS Neuro Solutions, and Restorative Brain Clinics. DMB Daniel Blumberger has received research support from the CIHR , NIH , Brain Canada and the Temerty Family Foundation through the CAMH Foundation and the Campbell Research Institute . He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd., and he is the principal site investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work was supported by the Ontario Mental Health Foundation (OMHF) , the Canadian Institutes of Health Research (CIHR) , the National Institutes of Mental Health (NIMH) and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute . RHM reports no conflicts of interest.

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