Authors: M. L. Cao, Y. X. Qin, N. Shao, C. Y. Zhang, L. L. Deng, X. R. Xu, Q. Liu, X. Yang
Categories: Case Report, Atypical myasthenia gravis, Distal myasthenia gravis, Hand weakness, Myasthenia gravis
Source: Journal of Medical Case Reports
Myasthenia gravis, which initially presents with prominent distal muscle weakness, is rare and is referred to as distal myasthenia gravis. Despite its clinical significance, the diagnosis of distal myasthenia gravis is often delayed or missed owing to mild and atypical symptoms.
We report the case of a 52-year-old ethnic Han woman who presented with task-related isolated transient right-hand weakness that began 15 years ago and lasted for 9 years without aggravation or improvement. In subsequent years, she developed right-hand stiffness with limited dexterity. More recently, this developed into bilateral hand weakness and simultaneous generalized weakness with ambulation, prompting suspicion of myasthenia gravis. Under Hertz repetitive nerve stimulation, the right facial nerve, right accessory nerve, right ulnar nerve, right radial nerve, and right median nerve showed decrements between 19.5% and 35.4%. Tests for anti-acetylcholine receptor antibodies were positive. The patient was diagnosed with distal myasthenia gravis, which evolved into generalized myasthenia gravis.
Distal myasthenia gravis can present with isolated and transient hand weakness as a lone symptom, and can persist for years before typical myasthenia gravis symptoms appear. The inclusion of myasthenia gravis in the differential diagnosis is necessary in patients with isolated distal weakness.
Keywords: Myasthenia gravis, Distal myasthenia gravis, Hand weakness, Atypical myasthenia gravis
Myasthenia gravis (MG) is a common autoimmune neuromuscular junction disease that manifests as weakness and fatigue of the affected skeletal muscles. Extraocular, bulbar, and proximal limb muscles are commonly involved, while the distal limb muscles are generally unaffected or minimally affected. MG with prominent distal muscle weakness and fatigability with a fluctuating course is rare and is referred to as distal myasthenia gravis (DMG) [1]. Here, we report a case of DMG with episodic right-hand weakness as the only manifestation for more than a decade prior to the diagnosis of MG. We report this case so as to add to the clinical spectrum of MG variations. We also conducted a literature review of DMG to improve the clinical understanding of this disease.
A 52-year-old right-handed ethnic Han woman presented with incidental transient right hand and grip weakness, which was first discovered 15 years ago after difficulty opening her front door. Her intermittent hand weakness persisted for 1–2 times/month, lasting for a few minutes per episode with a return to baseline. Weakness was precipitated solely by attempts to unlock the door. Otherwise, she had intact motor function (that is, unscrewing bottle caps, holding objects, cooking, and writing). Her symptoms did not worsen or improve over the last 9 years. She had visited the hospital twice, but no definitive diagnosis had been made at the time of assessment. Subsequently, she developed right-hand stiffness, including an inability to write or hold a pen. This was exacerbated by cold weather and alleviated by warm weather. She did not seek further medical attention due to non-disabling symptoms. In the preceding 2 years, the patient developed weakness with ambulation, finally prompting reevaluation. In addition, the patient had no special medical history or concomitant disorders, no family members with similar diseases, and no special social or phychosocialhistory.
Physical examination of the right hand showed finger flexion of 5−/5, finger extension of 5−/5, hand abduction of 5−/5, and hand adduction of 5−/5 [Medical Research Council (MRC) scale reference]. Fist clenching and finger extension fatigue tests were positive. Her left hand and left upper extremity were fully intact, without evidence of weakness. Examination of the lower extremities revealed proximal hip flexor weakness (5−/5− bilaterally) with an abnormal squat fatigue test (< 6 consecutive standing squats).
Electrographically, repetitive nerve stimulation (RNS) at 3 Hertz (Hz) showed a 20.7% decrement of the right orbicularis oculi, a 24.4% decrement of the right trapezius, a 19.5% decrement of the right abductor digiti minimi, a 23.2% decrement of the right brachioradialis, and a 35.4% decrement of the right abductor pollicis brevis. Serum antibody testing confirmed positive acetylcholine receptor antibody (AchR-Ab) > 20.00 nmol/L (Elisa assay, normal reference < 0.45 nmol/L). Chest computed tomography (CT) revealed no thymic hyperplasia or thymoma. It should be mentioned here that the alpinebiomedaps-KEYPOINT/6ch amplifier is a device for performing electromyography (EMG) tests on our patient.
A definitive diagnosis of generalized myasthenia gravis (GMG) was established. The patient was treated with pyridostigmine bromide (60 mg once a day) and showed clinical improvement. We also recommended that patient take steroid hormone therapy, but she refused for fear of the side effects of obesity. Azathioprine 100 mg once a day was then added after mercaptopurine methyltransferase activity resulted in the wild-type. At the 42-month follow-up, her symptoms were well controlled with this regimen, with normalization of lower extremity strength as well as fist clenching and squatting fatigue tests.
In patients with MG, eyelid ptosis is often the first symptom to appear and may be accompanied by bulbar, mid-axial, or proximal weakness [2]. Distal limb involvement usually occurs in the later stages of the disease. Early onset muscle weakness in the distal limbs as the main manifestation of MG is infrequent.
DMG has been previously described only in case reports [3–12]. Harvey et al. [13] first reported this clinical entity in 1948. Early cases revealed that patients presenting with distal muscle weakness as the first symptom of MG are exceptionally rare. Most of these patients had distal weakness in the hands and forearms, rather than weakness in the lower extremities (Table 1). Extensor, flexor, and abductor weakness of the hand or wrist were the most common symptoms in patients with DMG [1, 4, 11, 12]. Later reports provided insight into the possibility that isolated hand weakness could persist for years with minimal fluctuation prior to the manifestation of typical patterns of MG weakness [9, 11].
To date, three groups have retrospectively reviewed DMG. Nations et al. [1] analyzed the clinical symptoms of 236 patients with MG and defined DMG as distal extremity weakness exceeding proximal weakness by at least one MRC grade during the disease course. According to this criterion, the authors diagnosed nine cases of DMG, accounting for 3% of the total cohort. Most patients with DMG had hand weakness as the main manifestation (77.8%), with three patients presenting with hand weakness as the first symptom (33.3%) and one patient presenting with hand weakness as the only symptom (11.1%).
Similarly, we describe a patient with right-hand weakness while operating her door lock. We suspect that the flexor muscles of the thumb and index finger and pronator teres muscle were predominantly involved. This was confirmed using RNS testing. In a review of the literature, we found that most patients with upper-extremity involvement had weakness in the right hand. We speculate that this is related to the key role that handedness plays; any subtle weakness in one’s dominant hand is likely to be unmasked by routine and trivial tasks.
In 2003, Werner et al. [14] followed the evolution of 84 patients with MG over a 20-year period and found that 6 patients showed a predominance of muscle weakness and fatigability in distal muscles; 4 of these 6 patients developed distal muscle weakness late in the course, while 2 patients had distal muscle weakness as the first symptom. Most of the six patients (83.3%) had distal limb weakness characterized by hand muscle weakness, and only one patient (16.7%) had lower limb weakness. These trends were also reflected in another study conducted in 2017, supported by electrographical data [15]. Importantly, there was no difference between patients with DMG and other types of MG in terms of age at onset, gender, or response to treatment [14].
Despite this body of literature, DMG remains highly susceptible to clinical underdiagnosis and misdiagnosis [9]. Diagnosis was missed in our patient because of atypical presentation and mild symptoms. Clinically, the initial phenotype of our patient appeared to be “episodic,” with her complaining of right-hand weakness only with specific task-related skills after work (that is, key-in-lock), but otherwise reported normal motor function. We believe that this so-called episodic weakness is a diagnostic trap. That is, although it appeared to be “episodic,” it was actually weakness exposed at the end of the day during an activity that required skilled use of the intrinsic hand muscles. Moreover, her fluctuating weakness remained stagnant for 13 years, suggesting that patients with DMG may have a quiescent course in the early stages that escapes clinical detection.
Diagnostically, this case was further complicated by clinical symptoms, which seemed inconsistent with established electromyography (EMG) principles. It is a well-known phenomenon that increasing the room temperature can help increase the positive rate of RNS [16]. However, in our patient, weakness of her hands was aggravated by the cold weather. Distal limb weakness that worsens after exposure to cold is mostly seen in ion channel diseases, such as myotonic dystrophy [17, 18]. However, no published literature exists on the relationship or mechanism of MG muscle weakness induced by cold climate.
Furthermore, when looking back at the early stages of the disease, it is important to differentiate the patient’s episodic hand weakness from task-specific dystonia (TSD). TSD is characterized by tension, spasms, tremors, or other involuntary movements that occur with frequent repetition and performance of specific tasks. For example, writing spasms are commonly seen in stenographers [19]. However, in this case, the patient’s key twisting does not involve highly repetitive movements and only presents as weakness without convulsions, tremors or other discomfort, which is inconsistent with TSD.
We subsequently reviewed the literature on RNS patterns in patients with DMG (Table 1). The positive rate of the median and ulnar nerve RNS recorded in the hand and forearm muscles in patients with DMG of the upper limbs was significantly higher than that of the proximal nerves because the diagnostic sensitivity of RNS for MG depends on the distribution of muscle weakness and the severity of the disease [20, 21]. Consistent with the literature, the RNS of the ulnar and radial nerves in our patient showed a significant decrease in the abductor pollicis brevis, abductor digiti minimi, and brachioradialis. Significant decreases in RNS were also recorded in the accessory and facial nerves, which may be related to the chronicity of the disease.
Serologically, anti-acetylcholine receptor antibody positivity is seen in up to 50% of ocular myasthenia gravis cases and 90% of GMG cases [22]. For DMG patients, as presented in Table 1, the positive rate of AchR-Ab was 72.2%. Only AchR-Ab has been reported in patients with DMG thus far, and unsurprisingly, our patient presented with AchR-Ab.
We report a case of DMG manifesting as isolated chronic hand weakness with diagnostic confirmation achieved only after the generalization of weakness. We reviewed the relevant literature to draw attention to this rare subtype of MG and highlight the need to consider this diagnosis in patients with distal extremity weakness.
The authors thank Prof. Liying Cui and Doctor Eileena J. Newton for providing critical suggestions and for revising the manuscript. The authors also thank the patient and her family for their cooperation with this study. Yang Xiao, chief physician, professor, and deputy director of the Department of Neurology, School of Clinical Medicine, Ningxia Medical University, has long been engaged in the diagnosis and treatment of autoimmune diseases of the nervous system.
Cao ML and Qin YX discovered this case and wrote the manuscript. Deng LL performed the RNS test. Shao N, Zhang CY, and Xu XR, Liu Q collected and analyzed the data. Yang X designed and revised the paper. All authors have read and approved the final manuscript.
This study was supported by the National Natural Science Foundation of China (81860250 by Yang X) and the 2021 Innovation and Entrepreneurship Project for Returned Overseas researchers in Ningxia (2021–352).
All data have been included in the manuscript. No additional data are available.
This retrospective study was approved by Review Board of General Hospital of Ningxia Medical University of Science and Technology and written informed consent was waived. This study was carried out according to the Declaration of Helsinki.
Written informed consent was obtained from the patient for publication of this case report and any accompanying forms. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors declare no potential competing interests.
All data have been included in the manuscript. No additional data are available.