Patient information

A 30-year-old male presented to our university hospital with recurrent weakness in both the upper and lower extremities. This weakness began 6 months before visiting our hospital and occurred one to three times per month, usually being most severe in the morning upon waking. The weakness gradually improved after resting for approximately 6 hours. The patient reported severe weakness that hindered eating with a spoon and walking. However, he did not experience any difficulty in breathing, speaking, swallowing, or eye movements. The patient reported feeling fatigued 2 to 3 days before each episode of weakness. Additionally, he had experienced muscle pain in both legs the day before the weakness occurred. He had not engaged in strenuous exercise or any physically demanding activities the day before his hospital visit. On the day of his visit, he experienced weakness in the bilateral upper and lower extremities upon waking in the morning.

Diagnostic assessment

His vital signs were stable, with normal blood pressure, heart rate, and body temperature. An echocardiogram showed no abnormalities. Physical examination revealed mild, symmetrical motor weakness in both proximal and distal muscles of the bilateral upper and lower extremities, with a Medical Research Council grade of 4. Muscle atrophy and fasciculation were not observed. Sensory function was intact, and tendon reflexes were normal in the upper and lower extremities. No pathologic reflexes, such as the Babinski sign and ankle clonus, were observed.

1. Differential diagnosis

Diseases that may cause recurrent weakness were considered with the following differential diagnoses.

1) Multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that causes demyelination in the brain and spinal cord and disrupts normal nerve conduction [1]. Clinically, MS is characterized by relapse and remission, where neurological symptoms worsen acutely (relapse) and then partially or fully recover (remission) [2]. However, the disease often progresses gradually. A typical MS relapse develops over 24 to 48 hours and peaks within several days. In our patient, the weakness improved approximately 6 hours after symptom onset, which differed from the typical course of MS.

2) Neuromuscular junction disorders (myasthenia gravis or Lambert–Eaton myasthenic syndrome)

Neuromuscular junction disorders are characterized by intermittent muscle weakness. In patients with myasthenia gravis, muscle weakness worsens with activity and improves with rest. In contrast, Lambert–Eaton myasthenic syndrome causes weakness that is most severe at the onset of activity but improves progressively with repeated muscle use. However, our patient experienced muscle weakness upon waking, with symptoms improving after approximately 6 hours of rest. This presentation differed from typical neuromuscular junction disorders. However, owing to the varying clinical symptoms of muscular junction disorders, this condition was still considered. Electrodiagnostic and blood tests were conducted to rule out these disorders.

3) Thyrotoxic periodic paralysis

Thyrotoxic periodic paralysis (TPP) is characterized by the sudden onset of symmetrical weakness caused by hyperthyroidism [2]. Hypokalemia typically occurs during these attacks [2]. TPP usually develops rapidly early in the morning or late in the evening [2]. Although weakness due to TPP is typically confined to the lower extremities, it can also affect the upper and lower extremities [2]. TPP is a rare disorder; however, owing to its similarity to the clinical presentation of our patient, it was considered.

4) Hypokalemic periodic paralysis

Hypokalemic periodic paralysis is a genetic disorder caused by mutations in skeletal muscle ion channels, usually involving calcium or sodium channels [3]. It is characterized by episodes of sudden muscle weakness, often triggered by intense physical activity or the consumption of a high-carbohydrate meal. During these episodes, patients experience acute, generalized, or localized flaccid paralysis accompanied by hypokalemia, which can persist for several hours before resolving spontaneously. Most cases are hereditary or familial. To diagnose hypokalemic periodic paralysis, hypokalemia alongside paralysis onset is confirmed, and other potential causes of recurrent hypokalemia, such as renal tubular acidosis and thyroid, renal, and adrenal dysfunction, are excluded.

5) Hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant genetic disorder characterized by recurrent episodes of monoparesis and sensory loss, frequently triggered by focal nerve compression or trauma [4]. Pressure on a peripheral nerve can cause localized weakness and sensory deficit [4]. HNPP commonly affects nerves vulnerable to compression, such as the peroneal nerve at the fibular head, the median nerve at the wrist, and the ulnar nerve at the elbow, resulting in muscle weakness. In our patient, weakness occurred without peripheral nerve compression and was observed in the proximal and distal muscles of the bilateral upper and lower extremities. Therefore, the likelihood of HNPP was considered low.

6) Spinal dural arteriovenous fistula

A spinal dural arteriovenous fistula (AVF) is the most common vascular malformation of the spinal cord [5], typically presenting with intermittent recurring weakness as the initial symptom [5]. Although a spinal dural AVF predominantly affects the thoracolumbar region, causing weakness in the lower limbs, it can also occur in the cervical region, leading to weakness in the upper and lower extremities. A spinal dural arteriovenous shunt is located within the dura mater, near the spinal nerve root, where arterial blood from the radiculomeningeal artery flows into the radicular vein [5]. Increased spinal venous pressure impairs normal spinal vein drainage, causing venous congestion and progressive myelopathy [5]. In our patient, weakness was the only symptom observed, with no other signs of myelopathy, and deep tendon reflexes were normal. However, in cases of mild myelopathy, weakness may be the sole presenting symptom and deep tendon reflexes may be less pronounced or absent. Therefore, spinal dural AVF was still considered.

2. Diagnosis and management

Brain and whole-spine magnetic resonance imaging revealed no abnormalities. Nerve conduction studies and electromyography, including repetitive nerve stimulation at 3 Hz and 20 Hz, demonstrated no dysfunction in the peripheral nerves of the upper and lower extremities. Acetylcholine receptor-binding antibody test results were negative.

Potassium levels were reduced to 2.8 mEq/L (range, 3.6–5.0 mEq/L), while sodium (141 mEq/L; range, 135–145 mEq/L) and chloride (101 mEq/L; range, 96–106 mEq/L) levels remained within the normal range. Thyroid function tests showed a decreased thyroid-stimulating hormone (TSH) level of 0.02 mIU/L (range, 0.50–6.80 mIU/L) and elevated triiodothyronine and free thyroxine levels of 252 ng/dL (range, 80–170 ng/dL) and 2.20 ng/dL (range, 0.75–2.00 ng/dL), respectively. A thyroid autoantibody panel revealed elevated thyroid peroxidase antibody and TSH receptor antibody levels of 741.45 U/mL (range, 0–60 U/mL) and 2.12 IU/L (range, 0–1.5 IU/L), respectively, and normal anti-thyroglobulin antibody levels of 10.02 U/mL (range, 0–60 U/mL). Thyroid ultrasonography revealed an enlarged thyroid with increased vascularity. A thyroid scan using technetium-99m pertechnetate revealed diffuse enlargement of both lobes with enhanced trapping.

The patient was diagnosed with TPP secondary to Graves disease. As hyperthyroidism was identified as the cause of the paralysis, hypokalemic periodic paralysis was ruled out. The patient received oral potassium chloride (600 mg) three times daily for 1 week, along with methimazole (20 mg/day).

Clinical course

At the 5-week follow-up after treatment initiation, the patient had achieved a euthyroid state and potassium levels had returned to normal. No recurrence of weakness was observed over the subsequent 2 years.

Discussion

TPP is a rare sporadic disorder that primarily affects Asian males with hyperthyroidism, typically between the ages of 20 and 39 years [2]. The incidence of TPP in Chinese and Japanese patients with thyrotoxicosis is approximately 1.8% and 1.9%, respectively, whereas the incidence is reported to be between 0.1% and 0.2% in North America [2]. The condition exhibits a strong male predominance, with male-to-female ratios ranging between 17:1 and 70:1 [2]. TPP is a manifestation of thyrotoxicosis that is most associated with Graves disease [2]. Although not clear in this patient, common clinical features of hyperthyroidism include thyroid enlargement, weight loss despite increased appetite, rapid or irregular heartbeat (palpitations), hyperhidrosis, and nervousness or anxiety [6]. Additional symptoms may include tremors, fatigue, heat intolerance, and frequent bowel movements [6]. TPP should be considered in patients with hyperthyroid symptoms and recurrent episodes of muscle weakness.

However, the precise mechanisms underlying TPP remain unclear. Skeletal muscles store most potassium in the body (approximately 2,600 mmol) and play a key role in maintaining extracellular potassium balance [7]. This balance is primarily maintained by the sarcolemmal sodium-potassium ATPase pump, which facilitates potassium movement into cells [2,8]. Thyrotoxicosis enhances the transcription of genes encoding this pump and increases its intrinsic activity and overall function [2,8]. Additionally, inward-rectifying potassium (Kir) channels facilitate potassium entry into muscle cells [9]. Thyrotoxicosis further amplifies Kir channel activity, causing excessive potassium influx from the extracellular space into cells [10].

During a paralysis episode, patients with TPP experience recurrent transient weaknesses ranging from mild weakness to complete paralysis [2]. Weakness following TPP is often more pronounced in the proximal muscles, particularly in the lower extremities, [2]. In severe cases of TPP, respiratory failure may occur, necessitating ventilator assistance. Additionally, fetal arrhythmias, including ventricular tachycardia, ventricular fibrillation, sinus arrest, and atrioventricular block, are observed in patients with TPP [11]. Although patients with TPP typically regain muscle strength between attacks, weakness may persist in recurrent episodes [12]. TPP treatment involves correcting hypokalemia and managing hyperthyroidism [2].

TPP-induced weakness is treatable; however, symptoms can worsen after recurrent attacks. Clinicians should be knowledgeable about TPP and consider it in patients presenting with related symptoms.

Article information

Ethics statement

The study was approved by the Institutional Review Board (IRB) of Yeungnam University Hospital (IRB No: 2025-01-026). Written informed consent for the treatment and publication of this case report was obtained from the patient.

Conflicts of interest

Mathieu Boudier-Revéret has been an editorial board member of Journal of Yeungnam Medical Science (JYMS) since 2021. Min Cheol Chang has been an associate editor of JYMS since 2021. He was not involved in the review process of this manuscript. There are no other conflicts of interest to declare.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (Grant No. RS-2023-00219725).

Author contributions

Conceptualization, Data curation Methodology Investigation: SHA, MCC; Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation: MCC; Writing-original draft: SHA, MBR, SY, MCC; Writing-review & editing: SHA, MBR, SY, MCC.

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