Differential Response to Corticosteroids in Immune-Mediated Myokymia vs Grouped Fasciculation Discharges

Abstract

Myokymia and grouped fasciculation discharges (GFD) are electromyographic manifestations of peripheral nerve hyperexcitability syndromes. This case series explores the differential response to corticosteroids in patients with myokymia compared to those with GFDs. Six patients were included in this report: three with predominant myokymia and three with predominant GFDs, reviewed between March 2023 and February 2024. Electromyographic examinations were performed on various muscle groups, with the gastrocnemius EMG findings serving as an index. The neurologist conducting the EMG was blinded to the clinical history. Patients with predominant myokymia showed a positive response to corticosteroids. In contrast, patients with GFDs, characterized by non-rhythmic, irregular discharges, exhibited a limited response requiring higher immunotherapy. This study potentially highlights the importance of EMG in guiding treatment decisions, demonstrating that patients with myokymia respond well to corticosteroids due to underlying autoantibody-mediated potassium channel dysfunction.

Introduction

Involuntary muscle twitching, when intermittent, is usually fasciculations, while continuous twitches often suggest myokymia, neuromyotonia, or high-frequency fasciculations grouped under peripheral nerve hyperexcitability syndrome (PNHS).[1] Myokymia presents as rhythmic or semi-rhythmically with a high intra-burst frequency (5–60 Hz), while grouped fasciculation discharges (GFDs) are irregular with a lower intra-burst frequency.[2] The source of both these potentials has been extensively discussed in the literature, with the cause being ectopic potential generation, modified refractory periods, or changes in the membrane potentials.[3,4,5,6] Given their origin from the motor unit, earlier literature has occasionally grouped both together. Currently, there is no literature on the preferred immunotherapy regimen based on the type of underlying spontaneous muscle activity that arises due to immune pathophysiology. This knowledge can create a significant impact, especially in triaging patients to more effective therapy and in lower socioeconomic countries with limited access to the more expensive immunotherapies. We present a series of cases with myokymia or GFDs and propose that patients with PNHS, electromyographically characterized by myokymia, have a positive response to steroids.

Case Report

Consecutive patients aged more than 18 years presenting with acute to subacute continuous muscle twitching (peripheral nerve hyperexcitability) were reviewed in the inpatient or outpatient departments of a tertiary care center in Chennai by a member of the neurology team between March 2023 and February 2024. They were included in the myokymia group or the GFD group based on the electromyographic findings after informed consent. Inclusion into the myokymia group was done if myokymia was present along with GFDs, and inclusion in the GFD group was done if only GFD (including doublets, triplets, or multiplets) were present. Patients with concurrent motor neuron disease, structural central nervous system (CNS) lesions, or those on concurrent immunotherapy prior to electromyography (EMG) were excluded. This report included six cases, of which three patients were in the myokymia group [Figure 1] and three in the GFDs group [Figure 2]. Sampling was performed in the following muscle groups for all patients: Vastus lateralis, gastrocnemius, tibialis anterior, deltoids, and abductor pollicis brevis. All four quadrants from insertion points were examined for a standardized duration. The neurologist performing the EMG study (Nihon Kohden, MEB-9400k machine) was blinded to the clinical history and findings. The patient demographic characteristics and clinical features are described in Table 1, while electrophysiology results, including EMG findings, treatment, and outcomes, are listed in Table 2. All patients underwent routine blood tests, (hemogram, liver, renal, glycemic, lipid, and thyroid profiles), infective (HIV 1, 2, Hepatitis B and C), and immune workup (erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody and profile and Angiotensin-converting Enzyme (ACE) levels). Chest X-ray and an ultrasound abdomen with pelvis were done for all patients. Whole body positron emission tomography scan was done for five of the six patients and was negative. With regard to immunotherapy, high-dose glucocorticoids (1g intravenous once daily [IV OD] methylprednisolone) were attempted initially in all of the cases, and then if required escalated to intravenous immunoglobulin (IVIG) at 2g/kg over 5 days or five cycles of plasma exchange every alternate day. Follow-up in the clinic was for at least 6 months for all patients, with all patients remaining asymptomatic. EMG was not repeated for any of the patients.

Figure 1.

Myokymia observed in EMG, represented in single and rastered tracing for patient 1 (a and d), patient 2 (b and e) and patient 3 (c and f). EMG: Electromyography

Figure 2.

GFDs (fasciculations, doublets, triplets, and multiplets) observed in EMG, for patient 1 (a), patient 2 (b), and patient 3 (c) GFD: grouped fasciculation discharge, EMG: Electromyography

Table 1.

Demographic and clinical characteristics

Age (years)	Sex	Duration (Days)	Symptoms	Comorbid	Medications	Antecedent Events	Infective workup	Whole body PET
Patients with Predominant Myokymia
43	M	20	Generalized twitching	Nil	Nil	Nil	Negative	Normal
58	M	7	Generalized twitching Distal limb pain	HTN	Telmisartan and amlodipine	Fever, generalized myalgia a month back	Negative	Normal
56	F	10	Generalized twitching (LL>) Memory disturbance	DM	Metformin (1g)	Nil	Negative	Normal
Patients with GFD
32	M	14	Generalized twitching	Nil	Nil	Nil	Negative	Normal
41	M	9	Generalized twitching	Nil	Nil	Nil	Negative	Not done
60	M	12	Generalized twitching Pain in lower limbs	HTN	Telmisartan and amlodipine.	Indigenous medicines	Negative	Normal

GFD: grouped fasciculation discharge, M: male, F: Female, HTN: Hypertension, DM: Diabetes Mellitus, LL: Lower limbs, PET: Positron emission tomography

Table 2.

Demographic, clinical, investigative and treatment characteristics of patients

	Autoantibodies	NCS	EMG	First line Rx	Response	2nd line Rx	Response	Na channel blockers
Patients with Predominant Myokymia
1	Negative	Normal	Myokymia+++ Fasciculation+	Steroids	Cessation of twitching in 2 days	NA	NA	Nil
2	Negative	Normal	Myokymia+++ Doublet + Multiplets +	Steroids	Cessation of twitching in 3 days	NA	NA	Phenytoin, started on the day of admission
3	Lgi1 + CASPR 2 +	SM axonal	Myokymia+++ Fasciculation+	Steroids	Cessation of twitching in 2 days	NA	NA	Phenytoin, started after EMG
Patients with GFD
4	Lgi1+	Normal	Fasciculation++ GFD +++	Steroids	Persistent symptoms	IVIG	Cessation of symptoms over 10 days	Phenytoin, started on the day of admission
5	CASPR2+	Normal	Fasciculation++ GFD +++	Steroids	Persistent symptoms	IVIG	Cessation of symptoms over 1 week	Phenytoin, started on the day of admission
6	Negative	Normal	Fasciculation+ GFD +++	Steroids	Persistent symptoms	PLEX	Cessasion of symptoms over 1 week	Phenytoin, started after EMG

IVIG: intravenous immunoglobulin, GFD: grouped fasciculation discharge, EMG: Electromyography, PLEX: Plasma exchange, CASPR2: contactin-associated protein-like 2, LGi1: leucine-rich, glioma inactivated 1, Na: Sodium, NA: Not applicable, NCS: Nerve conduction study, +: occasional, ++: frequent, +++: abundant

Discussion

This report included patients with PNHS and compared the response to high-dose steroids between those electromyographically exhibiting myokymia vs those showing GFD only. All three patients with myokymia showed improvement with steroids. This differential response to steroids, in patients exhibiting myokymia compared to those with grouped fasciculations, has not been previously reported. We conducted a literature review to interpret this variance in response. Both myokymia and GFD can arise from proximal or distal parts of the motor units, but are differentiated by their rhythmicity.[3] It is, hence, important to understand the mechanism behind the rhythmicity of myokymia, which can explain the differential response to steroids.

The rhythmicity is determined by the after-hyperpolarization phase of the soma dendritic compartment, during which the net membrane current continues to be outward or in a hyperpolarizing trend due to the presence of an inflow of potassium current. When the calcium levels are increased or potassium inflow is decreased (secondary to potassium channel dysfunction), the membrane gets recurrently depolarized, at a threshold above the resting membrane level. This process repeats rhythmically, so that a brief excitation can trigger self-sustained repetitive firing. This state of the neuron, where the steady state is achieved at two voltages, one below and one above the threshold, is called bi-stability and contributes to the rhythmicity of myokymia[4] [Figure 3]. The time-locked rhythmic firing of multiple motor units in myokymia is probably due to extracellular accumulation of potassium, secondary to repeated firing. This lowers the potassium equilibrium of neighboring motor units, converting them from normal to bistable neurons, leading to a vicious cycle.[4]

Figure 3.

Normal membrane action potential waveform (Blue), action potential of a bistable neuron (green), and membrane potential when exposed to steroids (red). ms: millisecond, mv: millivolts

In line with this background, the positive response to steroids in myokymia is likely attributable to their impact on membrane potential by diminishing its excitability. Specifically, the excitation threshold of the membrane is elevated, and the potential-dependent excitability is shifted toward a more hyperpolarized state, thereby prolonging the after-hyperpolarization phase of neurons. This phenomenon may result from alterations in membrane permeability or changes in ion concentrations, particularly intracellular potassium levels.[7] The association of steroids with hypokalemia further corroborates their influence on membrane potential dynamics.[8] Conversely, in motor units producing GFDs, the neurons are non-bistable where an ectopic stimulus arises from a demyelinated nerve segment, producing action potentials whose after-hyperpolarization phase is short and non-responsive to steroids. This suggests that steroid responsiveness in myokymia may be due more to membrane-stabilizing effects than immune modulation.

Conclusion

Through this observation, we propose the utility of using an EMG to decide the use of a potentially less expensive treatment modality in patients with undulating muscle twitching due to myokymia. The limitation of this report is its small sample size, and therefore, the conclusions drawn are exploratory and hypothesis-generating. Future prospective studies with larger cohorts are warranted to validate these findings.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.