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Received date: 02/05/2025 Published date: 07/06/2025 Case Report

Bilateral Ocular Neuromyotonia and Epilepsy -Two Neurological Complications in One Patient with Systemic Connective Tissue Disease

Andrija Kostic¹, Milica Pantic², Nikola Savic³

¹Clinic of neurology, KBC “Dr Dragiša Mišović Dedinje”, Belgrade, Serbia
²Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
³Department of Health Studies, Singidunum University, Faculty of Health and Business Studies, Valjevo, Serbia

*Corresponding author

Andrija Kostic, Clinic of neurology, KBC “Dr Dragiša Mišović Dedinje”, Belgrade, Serbia

DOI: 10.55920/JCRMHS.2025.10.001452

Abstract

Introduction: Ocular neuromyotonia (ONM) is a rare neurological condition with paroxysmal diplopia due to myotonic contraction of extraocular muscle as its main clinical feature. It can involve almost any extraocular muscle. It occurs most often after the application of radiation therapy in the region of the neck and head, then with compression of nerves of vascular or meningeal origin, with autoimmune disease, and it can also be of idiopathic origin. In the following case report, we describe bilateral ocular neuromyotonia most likely of autoimmune origin (Rheumatoid arthritis).

Case outlines: The female patient, 45 years old, presented herself for a neurological exam, because of paroxysmal attacks of strabismus and diplopia. After additional clinical explorations in hospital conditions, ONM with comorbid rheumatoid arthritis (RA) and epilepsy was diagnosed. In further clinical follow-up, there was complete resolution of the ocular symptomatology after dual antiepileptic drug therapy.

Conclusion: Bilateral ONM is a rare condition that can be encountered in clinical practice. Forms caused by autoimmune diseases and with another neurological comorbidity has not been described so far. Treatment of such forms can be challenging. Beside the efficient RA therapy, use of a higher dose of the antiepileptic drug or a combination of two membrane stabilizers should be considered.

Keywords: bilateral ocular neuromyotonia; epilepsy; rheumatoid arthritis, autoimmunity

Introduction

Ocular neuromyotonia is a rare neurological condition that has paroxysmal diplopia due to myotonic contraction of extraocular muscle as its main clinical feature [1]. This disease was described in 1971 by Ricker and Mertens as idiopathic paroxysmal diplopia. During the duration of the diplopia episode, they observed a tonic unilateral exodeviation with restriction of elevation and abduction with increased activity of the medial and inferior rectus eye muscles. The following year, Papst described a patient with the same symptoms but with a disorder in the functioning of all four muscles (m. rectus medialis et lateralis, superior et inferior). Using electromyoneurography (EMNG), they observed a neurogenic pattern of neuromyotonic activity that is the result of spontaneous electrical activity in the unstable membrane of motor nerves, which is further followed by ephaptic transmission of electrical activity to surrounding nerves [2,3]. ONM can affect almost any extraocular muscle. It occurs most often after the application of radiation therapy in the region of the neck and head, then with compression of nerves of vascular or meningeal origin, with autoimmune diseases (myasthenia gravis, thyroid gland diseases, systemic connective tissue disease-s (CTD), and can also be of idiopathic origin [4]. In the following case report, we describe bilateral ONM of autoimmune origin.

The patient gave written consent for the publication of the article.

Case Report

The patient is 45 years old Causasian woman, presented herself for a neurological exam in February 2023 after a generalized tonic-clonic seizures and paroxysmal strabismus. Since she has been treated for twenty years for an “idiopathic form of epilepsy”, she received levetiracem therapy at a dose of 2000 mg per day. But due to the paroxysmal strabismus, which we considered not to be an epi phenomenon, the patient was admitted to the Neurology Hospital "Dr Dragiša Mišović" in Belgrade. The patient had first documented seizure at the age of 24. In the clinical course, she had several generalized tonic-clonic seizures, in therapy she used levetiracem. Until this hospitalization, she was managed as idiopathic generalized epilepsy, although the pattern of attacks did not have a circadian rhythm, the onset of the disease was not typical, and the EEG did not have a specific pattern. Paroxysms of strabismus with accentuation on the right eye and diplopia have been present from the age of 36 (Figure 1: a,b,c,d). In the beginning, they were rare, once a month, but at the time of admission, they have become everyday. We emphasize that the patient has been treated for rheumatoid arthritis (RA) since she was 20 years old. She has had an elevated ANA titer for years (1:640). Initially, she was treated with NSAIDs and corticosteroids, mainly due to the unavailability of other therapy. Quinolones were introduced to therapy a few years ago. With this, she achieved a solid control of the arthritis. Of course, radiological (X-ray) and clinical signs of arthritis are visible. She underwent carpal tunel surgery on both sides in 2015. She was examined by a psychiatrist, who found increased anxiety and irritability, a tendency to somatization, and reduced frustration tolerance. She is allergic to penicillin. Family history indicates a positive heredity for arterial hypertension and RA. In the neurological exam, recurrent episodes of binocular diplopia, triggered spontaneously or more often, by prolonged looking to the side or up. Then the tonic deviation of both bulbs into convergence, more pronounced on the right, lasting 1 minute on average. The finding indicates a prolonged contraction of m. rectus medialis, which is innervated by the lower branch of the n. oculomotorius. The rest of the findings are in order.

Additional diagnostics

Serial EEG and EEG after sleep deprivation were without specific epi pattern, practically normal. An exam by a neuro-ophthalmologist was performed: primarily orthophoria, looking up (spontaneous and guided) causes crossed eyes and diplopia. An MRI with contrast was performed: a non-specific punctiform T2W/FLAIR hyperintense lesion in the left frontal subcortical area (Figure 2). MRI findings of orbits and extraocular muscles was normal. CDS MAV neat find. Laboratory analyses: B12, vit D3, fT4, TSH, TG, anti TPO, anti TG normal. ANA was positive from before. Anti VGKC lower than 4, negative (analysis done in a laboratory in Germany). Unfortunately, we were unable to perform other antibodies of interest. While we were waiting for the analysis, we gave ex iuvantibus systemic corticosteroids in a dosage of 1mg/kg for five days, which did not resolve the symptoms. We did not decide to administer corticosteroids for a longer period of time because the patient had received them before and despite that the autoimmune response did not decrease, but the side effects continued to increase.

Figure 1:
a) looking straight (normal)
b) forced look to the right which leads to neuromyotonic reaction (c and d).
c) looking straight, right bulb is in convergence and after 15 seconds the right bulb returns to its normal position. But when she looks to the left (d), the left bulb remains in the primary position.
d) looks to the left

Figure 2: MRI T2 axial: one unspecific punctiform lesion, left frontal subcortical.

The membrane stabilizer carbamazepine was introduced into the therapy, according to available data in the literature. The initial dose was 2 x 200mg. Since no myoclonic and apsence seizures have been observed before, we did not expect deterioration of seizure control. The neurological findings registered a reduction but not resolution of myotonic phenomena on the eye muscles, so carbamazepine was increased to 2x400mg.

The patient was discharged with therapy: levetiracem in a daily dose of 2x1000mg, carbamazepine in a daily dose of 2x400mg, with previous internist therapy. At the last check-up, complete resolution of the ocular symptoms was observed. During that period and onwards she was seizures free. A visit to a rheumatologist and immunosuppressive therapy escalation was suggested, but we did not receive that report until the writing of this review. In a telephone conversation, the patient told us that since she was discharged from our clinic she has not had any ocular symptoms or seizures, and that the rheumatologist did not correct the therapy because she does not meet the criteria according to the health insurance regulations.

Differential diagnosis: We considered early stage of Graves disease (thyroid hormones were normal), convergence spasm and conversion disorder (previous psychiatric report), Superior oblique myokymia (monocular, rhythmic contraction). The Heimann Beilshowsky phenomenon (HBF) is an interesting differential diagnosis. Namely, this phenomenon is characterized by monocular peduncular oscillatory activity, but which is a consequence of ipsilateral vision loss that persists for a longer period of time. It becomes more apparent with distance fixation and is inhibited by convergence or near fixation. In contrast, ONM is characterized by repetitive short episodes of diplopia secondary to unilateral involuntary spasms of one or more extraocular muscles innervated by one of the cranial nerves (n.oculomotorius, less often n.trochlearis and n.abducens).

However, what HBF and ocular neuromyotonia have in common is the main pathophysiological mechanism, that is, ephaptic (lateral) transmission, which is believed to underlie both diseases [11]. Ephaptic neural transmission is also the mechanism by which hemifacial spasm occur [12]. It’s also important to distinguish it from conversion disorder. Namely, conversion disorder is characterized by the manifestation of inexplicable physical symptoms that affect voluntary motor and sensory function in such a way that they indicate the existence of a neurological disease with an emphasis on the presence of intrapsychic conflicts that play a significant role in the initial onset of symptoms, exacerbation and maintenance over time. However, in the case of conversion disorder, careful observation and repeated clinical exams can reveal an atypical clinical presentation that does not correspond to a disease of the nervous system per se [13].

Discussion

The term ONM is used to describe a syndrome whose main symptoms are strabismus and diplopia due to myotonic contractions of extraocular muscle. The diagnosis can be overlooked in patients who complain of paroxysmal diplopia, which is why a careful examination of bulbar mobility is necessary. Pathophysiologicaly, a spasm occurs as a result of spontaneous firing of one or a group of nerves, with activation of the innervated muscles. This is further transmitted to nerves that innervate other muscles, forming a unique pathological circuit. This mechanism also exists in other neurological diseases, such as radiation plexopathy, peripheral and traumatic neuropathy, hemifacial spasm, where spontaneous firing occurs in demyelinated axon segments. Spontaneous firing of demyelinated axons has also been demonstrated in experimental animal models of neurological diseases. Continuous axon activity is followed by an increase in extracellular calcium, which can explain prolonged muscle activity in the form of spasms [5,6].

ONM has been described in patients previously exposed to head and neck radiotherapy and also in patients with malignancy of other tissues [7]. This disease has also been shown in long-term alcohol abuse, where alcohol-induced lesions of peripheral nerves are cited as the dominant mechanism of occurrence [8]. ONM can be caused by secondary and numerous primary diseases of the thyroid gland. Thus, it was described in Grace's disease, then in metastatic papillary carcinoma of the thyroid gland [9]. Completely, this disease can occur as a consequence of most diseases that lead in their clinical course, progressively, to nerve lesions [10].

Considering that the patient has RA and a positive ANA, since the age of 20, that she had her first GTC (generalized tonic-clonic seizure) at the age of 24, that ONM appeared at the age of 36, we wondered if these conditions might be related and autoimmune in origin. So far, one case of neuromyotonia and juvenile RA has been described [14], as well as a few cases with other sCTD. Regarding epilepsy, we did not find a connection with ONM, except that in this case they probably share the same pathophysiology. But there is an increasing number of papers linking RA and epilepsy. The development of epilepsy within RA patients is 1.27-fold higher than the control patients without RA (1.52 adjusted HR). Duration of non-steroidal anti-inflammatory drug (NSAID) therapy in RA patients negatively correlated with epilepsy development while patients with minimal NSAID therapy had a greater risk of epilepsy development. This suggests that limiting the inflammatory process induced by RA reduces risk of epileptogenesis. Offspring of women, who had RA during pregnancy, are at a significantly higher risk of developing childhood-onset epilepsy as compared to the offspring of women who developed RA post-pregnancy. Paternal RA is suggested to have a relatively low association to epilepsy development within offspring. These findings suggest that the inflammatory conditions induced within RA impact the intrauterine environment and increase the risk of epileptogenesis within children [15,16].

RA is an autoimmune inflammatory disorder characterized by the anti-IgG antibody (RF Factor) and anti-CCP antibody. It is associated with an upregulation of TNF-α, IL-1 and IL-6. These and cytokines in other autoimmune diseases lead to dysregulation of the immune response both in the periphery and in the CNS (central nervous system). Blood brain barrier (BBB) damaged by immune mechanisms becomes permeable to autoantibodies and cytokines. This further leads to the stimulation of microglia and astrocytes and the secretion of additional inflammatory factors. A smoldering inflammation is created, which is thought to be responsible for epileptogenesis, both directly and due to the creation of aberrant neuronal networks (brain plasticity). This mechanism is also present in ONM. And in addition, there is a direct influence of autoantibodies on the myelin sheath. Nerves damaged in this way are prone to ephaptic transmission. Therefore, autoimmune mechanisms could be at the basis of the development of both neurological conditions in our patient [17,18].

What can be a problem is the therapy of both diseases. Namely antiepileptic drugs are the drugs of choice. Carbamazepine (CMP), which is the most commonly recommended drug for OMN, can worsen some epileptic seizures (absence, myoclonic). Lacosamide might be a better choice for ONM, because it interacts less and has fewer side effects than CMP, and so far it has been shown to worsen myoclonic (rarely) but not absence seizures [13,19].

A case of a patient with idiopathic ONM who responded well to the use of acetazolamide, a carbonic anhydrase inhibitor used for the treatment of glaucoma, urinary retention, epileptic seizures (in combination with antiepileptics for additive effect) was described [12]. Secondary ocular neuromyotonias are treated in addition to the treatment of the primary disease.

Bilateral ONM is a very rare condition that can be encountered in clinical practice. Since it can be a consequence of numerous primary diseases that lead to the lesion of nerves, it is important to take it seriously, diagnose it at right time and start treatment. Autoimmune forms of bilateral ONM are less often, while the form with comorbid epilepsy has not been described so far, which reflects one of the importance of our presentation. Both conditions are lifelong, and for now, they share a common therapy. Therefore, the presence of this comorbidity makes it more challenging to treat because use of some antiepileptic drugs can make seizures worse e.g. carbamazepine exaggerates myoclonic jerks, absances and atonic seizures. In the case of comorbid epilepsy, we can talk about a globally lower threshold of neuronal excitation, so the use of a higher dose of the drug or a combination of two could be considered [20,21], which is the additional significance of our case report. Also, if we take into account that the patient has been suffering from RA since she was 20, from epilepsy since 24, and ONM since 36, and that the last two conditions are the result of RA, i.e. autoimmune-mediated, the question remains whether a more effective immunosuppressive therapy would be a solution for all? Which patients with systemic connective tissue disseases should be treated with highly effective therapy from the beginning, in order to prevent the development of CNS complications and the impact on the development of the fetus in pregnant patients? Further research is needed to answer these questions.

Conflict of interest: None declared.

Conclusion

MERS has been classically described in children with concomitant infections, mostly viral. An increasing number of cases have been reported in adults. When encountering a patient with a cytotoxic lesion of the corpus callosum, MERS should be considered as a differential diagnosis. However, etiologies with a worse prognosis and specific treatment must be ruled out. Furthermore, while the most characteristic presentation is associated with altered levels of consciousness, we present this atypical clinical case, which should be considered within the spectrum of clinical presentations of this condition

References

Journal of Clinical Case Reports, Medical Images and Health Sciences (ISSN 2832-1286) is a peer-reviewed journal dedicated to publishing clinical images from all sectors of medicine. The goal of this magazine is to disseminate information about new discoveries and treatments in science and medicine.

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