Abnormal spontaneous and evoked muscle activity occurs in neuromyotonia, but the disorder affects the peripheral motor nerves rather than the muscles. The first description in muscle was by Denny-Brown and Foley (1) as “undulating myokymia.” Isaacs (2) demonstrated that the continuous recorded muscle activity was generated by spontaneous activity in the peripheral portion of the motor nerves rather than in the muscles or spinal cord by showing that curare blocked this activity whereas general anesthesia did not.
In addition to neuromyotonia, many terms have been applied to this condition, including “armadillo syndrome,” “quantal squander,” “Isaacs syndrome,” and “Merten syndrome.” The continuous muscle activity at rest is usually called “myokymia” and the muscle spasm induced by sustained activation has been called “neuromyotonia,” “impaired muscle relaxation,” and “pseudomyotonia.” At the electrophysiological level, neuromyotonic discharges and myokymia are essentially the same thing except that in the case of neuromyotonia, the firing rates are higher and the amplitude may wane (3).
There are many situations in which damaged motor neurons may exhibit these phenomena, now grouped together as “peripheral nerve hyperexcitability” (PNH) disorders, but recent discoveries in autoimmune and genetic conditions have shed light on the underlying pathophysiology. It was known at an early stage that many of these patients had coexisting autoimmune disorders, including thyroid disease and myasthenia gravis. Some of these patients showed improvement with plasma exchange (4), and a radioimmunoassay developed from the green mamba snake toxin detected antibodies against voltage-gated potassium channels (VGKCs) in patients with acquired autoimmune neuromyotonia. Limbic encephalitis can also occur in patients with antibodies to VGKCs without neuromyotonia. However, in 1890, Morvan (5) described as “la chorée fibrillaire” a case in which neuromyotonia and encephalopathy occurred together. Cases of neuromyotonia manifesting insomnia, hallucinations, and behavioral disturbances are sometimes referred to as Morvan syndrome. Mutations in genes encoding VGKC subunits are now known to cause PNH in isolation and in association with episodic ataxias.
A very early description of neuromyotonia occurring in an extraocular muscle (the superior oblique) was published by Clark (6), but the term “ocular neuromyotonia” was introduced by Ricker and Mertens (7). Extraocular muscle electromyography established the fact that the induced spasms were neurogenic in origin.
Several years ago a patient complaining of intermittent diplopia was referred to me. The referring letter, which came from a senior neurologist who had been one of my teachers, pointed out that the patient appeared to have a mild unilateral third cranial nerve palsy but that during the examination the signs kept changing. I recalled a story told to me in San Francisco in 1990 by another mentor, William F. Hoyt, MD, about a man who, when driving, would see two hoods on his Buick when he moved his eyes back to primary position after looking through the rearview mirror. The patient I was asked to examine intermittently appeared to have a lateral rectus paresis as sustained adduction provoked spasm of the medial rectus. It was this latter phenomenon, not the mild third cranial nerve palsy with synkinesis, that caused his diplopia. I could also explain why his family members reported that occasionally the patient's eye looked “starey” following sustained upgaze when I noted dramatic lid retraction due to spasm of the levator palpebrae superioris.
Until that time, all published cases of ocular neuromyotonia had followed radiotherapy. My patient had an aneurysm compressing the third cranial nerve. This case was reported along with two others (8). The second patient, whose case followed radiotherapy, also had signs of a chronic partial third cranial nerve palsy with synkinesis at rest, such that the levator muscle was activated on downgaze (pseudo-von Graefe sign). The third patient, seen by Mr. Michael Sanders, my colleague in neuro-ophthalmology, appeared to have a spasm of the superior oblique muscle.
In ocular neuromyotonia, the neuro-ophthalmic manifestations always lessen when the patient is treated with relatively low doses of a membrane-stabilizing agent such as carbamazepine. Not only did the neuromyotonia in our second patient disappear with treatment, but the signs of synkinesis and the chronic partial third nerve palsy also improved. In this issue of the Journal of Neuro-Ophthalmology, Oohira and Furuya (9) describe a patient who also exhibited the association of third cranial nerve synkinesis and neuromyotonia, both regressing spontaneously and in parallel. The authors concluded, as did we (8) and Shults et al (10) that the synkinetic movements and the neuromyotonia may have a common etiology and that the synkinetic movements may not be due entirely to “hard-wired” misdirection. The improvement in the chronic third cranial nerve palsy with carbamazepine treatment in our second patient suggests that the carbamazepine may have alleviated a chronic neuronopathy as well as preventing the spasms.
Also in this issue of the Journal, Choi and colleagues (11) present an idiopathic case of third cranial nerve synkinesis and neuromyotonia. They use the term “aberrant regeneration” which, unlike the term “synkinesis,” implies an unverified pathophysiology. These authors also found that both the neuromyotonia and the signs of aberrant regeneration (lid retraction on downgaze) improved when the patient was treated with carbamazepine.
It is difficult to understand why any medication would have an impact on hard-wired anomalous innervation. Yet not all cases of ocular neuromyotonia show synkinetic phenomena and not all cases of synkinesis show neuromyotonic phenomena. Consider the following parsimonious hypothesis. Misdirected neurons have been damaged and undergo Wallerian degeneration. This process becomes arrested at some point and a new axon or axons have sprouted and succeeded in reinnervating an ocular muscle-the wrong one. A nerve with damaged but surviving neurons has the potential to exhibit neuromyotonic phenomena. This association may be more common than has been reported. Most patients with third cranial nerve neuromyotonia who I have examined have shown synkinetic as well as neuromyotonic phenomena. Perhaps there is a hard-wired hard core of genuine misdirection that will always persist, but these neurons are also liable to generate ephaptic transmission, which may be responsible for amplification of synkinetic movements. Such amplification would be readily attenuated by carbamazepine. An interesting question is whether the persistent activation is limited to the muscle that has undergone sustained activity or whether it spreads to other muscles.
Oohira and Furuya (9) also note involuntary eye closure in their patient at the onset of the spasm. This phenomenon is difficult to relate to the proposed schema, and I wonder whether it occurred to avoid diplopia (12).
Neuromyotonia is now explained physiologically as a disorder of cell membrane potassium channels, such that the axon can no longer maintain membrane stability. At rest this gives rise to myokymia. During sustained muscle activity, extracellular potassium accumulates and provokes neuromyotonic discharges. In the past, demyelination was proposed as the pathophysiologic basis of ocular neuromyotonia, but I do not think that this is very likely, at least not without contributions from other factors. Demyelination is not present in most causes of PNH. Furthermore, the condition in which demyelination and remyelination occurs most frequently in the ocular motor nerves is microvascular ischemic palsy, yet these patients never develop neuromyotonia. Radiotherapy is the most common cause of ocular neuromyotonia (50% of cases reported), and it is well known that in cases of post-irradiation plexopathy, myokymic and neuromyotonic discharges are seen in 80%, a finding used to attribute progression to irradiation rather than recurrent malignancy. The parallels between PNH disorders and ocular neuromyotonia are clear, but there are differences. Myokymia and neuromyotonia are almost always found together in peripheral nerve disorders, yet in the extraocular muscles we encounter two rather distinct syndromes: myokymia affecting only the superior oblique and neuromyotonia affecting any of the extraocular muscles.
In his Elegy to Sir Philip Sidney, the Elizabethan poet Matthew Roydon wrote:
I trow that countenance cannot lie,
Whose thoughts are legible in the eye.
The eyes can tell us more than a person's thoughts. Ocular neuromyotonia exemplifies what we can read about disease processes-if we know the language. The “countenance cannot lie,” but the observer can fail to comprehend.
1. Denny-Brown D, Foley JM. Myokymia and the benign fasciculation of muscular cramps. Trans Assoc Am Physicians
2. Isaacs H. A syndrome of continuous muscle-fibre activity. J Neurol Neurosurg Psychiatry
3. Gutmann L, Libell D, Gutmann L. When is myokymia neuromyotonia? Muscle Nerve
4. Sinha S, Newsom-Davis J, Mills K, et al. Autoimmune aetiology for acquired neuromyotonia (Isaac's syndrome). Lancet
5. Morvan A. De La choree fibrillaire. Gaz Hebd Med Chir
6. Clark E. A case of apparent intermittent overaction of the left superior oblique. Br Orthoptics J
7. Ricker VK, Mertens HG. Okulare neuromyotonie. Klin Monatsbl Augenheilkd
8. Ezra E, Spalton D, Sanders MD, et al. Ocular neuromyotonia. Br J Ophthalmol
9. Oohira A, Furuya T. Ocular neuromyotonia with spastic lid closure. J Neuroophthalmol
10. Shults WT, Hoyt WF, Behrens M, et al. Ocular neuromyotonia: a clinical description of six patients. Arch Ophthalmol
11. Choi KD, Hwang JM, Park SH, et al. Primary aberrant regeneration and neuromyotonia of the third cranial nerve. J Neuroophthalmol
12. Tay E, Plant GT. Unilateral involuntary eyelid closure induced by diplopia that did not remit with contact lens occlusion. J Neuroophthalmol