Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.


Introduction
The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. 1 TN has been reported in 2%-10% of patients with MS [2][3][4] and with an incidence 15-fold higher than in a general outpatient population. 4 A pontine lesion proximal to the trigeminal ganglia is often, but not always, observed on magnetic resonance imaging (MRI) in patients with MS and TN. 4 There remains disagreement in clinical practice regarding whether the presentation of a symptomatic central nervous system (CNS) lesion in the form of TN, accompanied by fulfillment of additional elements of the McDonald criteria (MC), is sufficient for the diagnosis of MS or whether such patients should instead be diagnosed with radiologically isolated syndrome (RIS). We present three patients with TN and demyelinating lesions suggestive of MS that highlight this diagnostic quandary and the unmet need for data to improve decisionmaking in such patients.

Methods
Of the 481 patients who underwent neurosurgical treatment for TN at the Toronto Western Hospital in Canada between June 2004 and May 2018, we retrospectively identified three patients with a diagnosis of TN according to the International Classification of Headache Disorders-3, 5 who also presented with MRI lesions highly suggestive of MS. All patients received longitudinal clinical and 3T MRI assessment approximately every 6 months or as needed as part of our routine follow-up care. An MS subspecialist neurologist (J.O.) reviewed all clinical records and MR images for evidence of events suspicious for demyelination and for 2017 MC 6 fulfillment. The study was approved by the University Health Network Research Ethics Board.

Cases
Demographic and clinical characteristics are summarized in Table 1.

Case 1
A 49-year-old woman presented with a 13-year history of TN in the left V2/V3 distribution. She had no prior history of additional neurological symptoms. Neurological examination was normal. Brain MRI revealed a lesion within the dorsolateral left pons presumed responsible for TN, multiple T2 hyperintense supratentorial lesions concerning for MS ( Figure  1(a)-(c)), and absent neurovascular contact with the trigeminal nerve. The patient was treated for TN and monitored clinically and radiologically and never received MS disease-modifying therapy (DMT). Ten years after presentation, neurological symptomatology remained restricted to TN and neurological examination remained unchanged. Brain MRI 5 years after presentation remained unchanged.

Case 2
A 68-year-old woman presented with a 22-year history of TN in the left V2/V3 distribution. She had no prior history of additional neurological symptoms. Neurological examination was normal. Brain MRI revealed a left pontine lesion presumed responsible for TN, multiple T2 hyperintense lesions concerning for MS (Figure 1(d)-(g)), and absent neurovascular contact with the trigeminal nerve. The patient was treated for TN and monitored clinically and radiologically and never received DMT. Seven years after presentation, neurological symptomatology remained restricted to TN and both neurological examination and brain MRIs remained unchanged.

Case 3
A 69-year-old woman presented with a 25-year history of left-sided TN in 2007 affecting V1-V3. She had no prior history of additional neurological symptoms. Neurological examination was normal. MRI revealed a pontine lesion presumed responsible for TN, multiple T2 hyperintense lesions concerning for MS including cervical and thoracic spinal cord lesions (Figure 1(h)-(l)), and absent neurovascular contact with the trigeminal nerve. The patient was treated for TN and was monitored clinically and radiologically and never received DMT. Fourteen years after presentation, neurological symptomatology had remained restricted to TN and neurological examination remained unchanged. Brain MRI remained unchanged 9 years after presentation.

Discussion
We highlight the diagnostic challenge presented by TN in the setting of concurrent MRI evidence of CNS demyelination suggestive of MS. Diagnosis of relapsing-remitting MS 6 can often be confirmed in patients presenting a clinically isolated syndrome (CIS) typical of MS-defined as an inflammatory event in the CNS developing acutely or subacutely with a duration of at least 24 hours. 6 "Focal brainstem syndromes" are considered typical of MS by the 2017 MC, yet are not enumerated or described. Although paroxysmal symptoms are not mentioned in the 2017 MC, prior iterations have mentioned that such symptoms, if characteristic of MS, might be considered a

Declaration of Conflicting Interests
The author declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: G.A. has received speaking honoraria, compensation for consulting services or participation in advisory boards from Sanofi, Merck, Roche and Horizon Therapeutics; travel support for scientific meetings from Novartis, Roche and ECTRIMS; is editor for