Thyrotoxic periodic paralysis (TPP) is one of the rare clinical manifestations in hyperthyroid patients characterized by muscle weakness and usually associated with subnormal to very low serum potassium levels [1]. TPP can occur with any form of thyrotoxicosis [2]. However, Graves’ disease is the most common cause of TPP in thyrotoxicosis and it is less commonly associated with thyroiditis [1-2]. Muscle weakness can range from mild weakness to life-threatening flaccid paralysis and can occur suddenly, with symptoms lasting from hours to days [3]. Although serum potassium levels are usually below normal in TPP, in very rare circumstances it may be normal leading to an entity called normokalemic TPP. The diagnosis of normokalemic TPP is more often overlooked and/or delayed because of a lack of awareness among physicians and associated mild symptoms of hyperthyroidism [4]. Here we present a case of a young adult Asian male with thyroiditis and TPP who was normokalemic during the acute phase of paralysis. 

Case Presentation

A 37-year-old Asian male patient presented to the emergency department with sudden weakness in both legs for six hours after waking up from sleep in the morning. He also complained of pain especially in both thighs making it difficult for him to move or walk. He felt a tingling sensation before pain and weakness appeared. The patient also complained of palpitations, tremors in his hands, and sweating. He denied weakness in other parts of the body, back pain, slurred speech, headache, dizziness, and changes in vision or hearing. There is no history of fever, trauma, cough, or other symptoms of upper respiratory tract infection. No prior history of vaccination was documented. He had no difficulty in urination and change in bowel habits such as constipation or diarrhea. 

The patient admits that he had suffered repeated attacks of limb weakness or paralysis for the last one week and that each paralytic attack lasted from one to two hours. He had noticed that his paralytic attacks usually appeared after exercise and resolved spontaneously without any medication. In the last few weeks, he admitted that he was quite busy at work, so he was worried about his current condition. There were no history of similar disorders or other endocrine or neurologic diseases in his family. He was recently diagnosed as having hyperthyroidism due to thyroiditis one month ago based on the result of neck ultrasonography from another hospital and was treated with oral thyrosol 20 mg and propranolol 10 mg three times daily.

On examination, his vital status was as follows: blood pressure, 120/70 mmHg; heartbeat, 107 bpm; body temperature, 36.4^oC; maintaining 98% oxygen saturation on room air, with clear consciousness. He appeared anxious and had slight tremors in both hands. There was a diffuse enlargement of the thyroid gland without any nodules on neck palpation. Neurological examination showed the weakness of the bilateral lower limbs with a muscle power score of 3. Muscle weakness was more severe in the hip region than in the ankle and pedis. Cranial nerve and sensory examination showed no abnormality. The other systemic examination was unremarkable. 

Laboratory examination revealed normal complete blood counts, kidney function tests, liver function tests, and serum electrolytes (including sodium, potassium, and calcium levels). However, the thyroid function test showed low TSH, and high FT4 levels (Table 1). A 12-lead electrocardiogram showed only sinus tachycardia (107 bpm). Chest x-ray showed a normal result. A working diagnosis of normokalemic thyrotoxic periodic paralysis was made based on clinical manifestations. He started to get observations and some therapies such as low-dose oral potassium chloride (KCL 8mEq) tablet daily and continuing previous treatment of hyperthyroidism with oral thyrosol 20 mg and propranolol 10 mg three times daily also therapies from the co-treating neurologist (mecobalamin, folic acid, and gabapentin orally). After 2 nights of hospitalization, his clinical condition improved, and serum potassium levels remain in a normokalemic condition. He was discharged with a scheduled follow-up in the internal medicine outpatient department.

Table 1: Hematological And Electrolyte Levels Tests of the Patient

TPP is a rare and potentially lethal complication of hyperthyroidism. Patients are usually young adults 20 – 40 years of age [5]. Even though primary autoimmune hyperthyroidism is predominantly in females, this manifestation is more common in male patients with a male-to-female ratio ranging from 17:1 to 70:1 [6]. TPP is more commonly reported in the Asian population, including patients of Japan, Chinese, Vietnamese, Korean, Filipino, American Indian, and Hispanic ancestry [7]. Previous literature shows that the incidence of TPP in China and Japan is 1.8% and 1.9%, respectively [8] in contrast, the incidence is 0.1% to 0.2% in the west and usually includes patients with an Asian background [9]. The characteristics of our patient are in accordance with this, which is a 37-year-old male patient of Asian descent especially Chinese background. The incidence of this case has indeed been widely said to occur in the third decade of life, unsurprisingly coinciding with the mean age of onset of Graves' disease [5]. Although most cases of thyrotoxicosis are associated, with TPP caused by Graves' disease, TPP can present with any thyrotoxicosis. Patients with TPP have been reported with thyroiditis, toxic adenoma, toxic nodular goiter, TSH-secreting pituitary adenoma, T4 or T3 ingestion, accidental iodine excess, de Quervain's subacute thyroiditis, and amiodarone therapy [1].

Much of the literature describes TPP as a triad of conditions characterized by muscle weakness in hyperthyroidism patients with low serum potassium levels. Muscle weakness usually affects the lower limbs [10] furthermore, more commonly in the proximal muscles than in the distal muscle [8]. Prodromal symptoms include muscle pain, stiffness, weakness, or cramping one hour to three days before paralysis. Prior to the presentation, most patients have less severe muscle weakness that resolves spontaneously. Sensory function, bowel and bladder function, facial expression, swallowing, and respiration are usually unaffected [5,9,10]. Precipitating factors include high carbohydrate diet, alcohol, high salt intake, trauma, rest after strenuous unaccustomed exercise, infection such as respiratory or urinary tract infections, emotional stress, and use of 2-adrenergic bronchodilators [2,5,9,10]. Patients usually experience attacks in the summer months, which may be due to increased outdoor activity and consumption of sweet drinks [10]. We found this characteristic of muscle weakness in our patient. He developed weakness in both legs, especially in the proximal muscle accompanied by prodromal symptoms such as pain and tingling. Also a few days earlier, the patient had similar complaints but resolves spontaneously without medicines. Precipitating factors may include our patient’s excessive exercise or emotional stress. 

Sodium, chloride, calcium, and potassium channels in the cell membrane are responsible for membrane excitability and muscle contraction. Further evidence suggests that increased activity of Na+/K+ ATPase can cause rapid movement of potassium into the cell from the extracellular space which eventually led to hypokalemia condition and contractility abnormalities of the muscles or paralysis. Overstimulation of the Na+/K+ ATPase pump in skeletal muscle cell membranes can be caused by excessive thyroid hormone levels [3,4,8-10]. Furthermore, it is possible that androgens may increase Na+/K+ ATPase pump activity, thus explaining the higher incidence in men [3]. In addition, insulin is another stimulator of the Na+/K+ ATPase pump as well. The hyper insulinemic response may explain the association of TPP with carbohydrate-rich meals and sweet snacks [1]. Genetic association in the pathogenesis of TPP has been reported, such as the HLA-DRw8 gene in Japanese patients, also A2BW22 and AW19B17 gene in Chinese patients [4]. Recent studies have shown that mutations in the KCNJ18 potassium channel genes are associated with TPP and predispose these patients to acute paralytic attacks [6]. This evidence has widely indicated that TPP results from a combination of genetics, hyperthyroidism, and some precipitating factors.

Although it is often associated with hypokalemia, it is not absolute. Several cases of TPP have been reported in patients with normal serum potassium levels. The first case describes a 36-year-old male patient with recurrent bilateral lower limb weakness [2]. He was found to have hyperthyroidism due to Graves’ disease with regular treatment, and normal potassium serum levels on admission (potassium: 4.4). After intravenous potassium 40 mmol in 1 L of normal saline was administered, he had a complete resolution of lower limb weakness within twelve hours. The second case describes a 27-year-old male with newly diagnosed but untreated Grave’s disease and TPP who was normokalemic during the acute phase of paralysis (potassium: 4.2) [4]. Potassium serum levels progressively diminished over the next few hours and days. However, it was not associated with a significant increase in weakness. This is in contrast to other publications which state that the severity of muscle weakness corresponds to the degree of hypokalemia [5,8,9]. He was administered low-dose oral potassium chloride (KCl) tablets during the hypokalemic phase and advised a low carbohydrate diet and a caution to avoid heavy or strenuous exercise, and he responded to this treatment. And the third case describes a 33-year-old Taiwanese male with hyperthyroidism and bilateral limb weakness that is more severe in the lower limbs than in the upper limbs. His potassium serum levels at the time were normal (potassium: 3.5) [8]. After intravenous potassium infusion (20mEq/L) with normal saline was prescribed, he felt a decrease in limb weakness. These findings include our case showing that the incidence of TPP is not always accompanied by low serum potassium levels in the acute phase of the disease.

In general, the management of TPP includes correction of hypokalemia and treatment of the underlying hyperthyroid state. During periodic paralysis and marked hypokalemia, immediate supplementation with potassium chloride is necessary to prevent major cardiopulmonary complications [1,3,5,8,]. Hypomagnesaemia and hypophosphatemia are commonly concomitant and may also require replacement [3,6,7]. The dose of KCl required varies between 40 and 200 mmol [5]. During potassium replacement, there is an increased risk of potentially fatal rebound hyperkalemia, especially at higher doses. Rebound hyperkalemia occurred in approximately 40% of patients of TPP, especially those who received > 90 mEq/ dL of potassium chloride within the first 24 hours [1,7,8]. Non-selective beta-blockers such as propranolol may be useful in preventing attacks of paralysis once the patient has started taking anti-thyroid drugs until a euthyroid state is achieved [7,8]. Usually, TPP does not recur once the patient is euthyroid. However, there is a case describing a Caucasian male with a known history of Graves’ disease who presented with TPP while he was euthyroid [6]. Ultimately, definitive treatment of hyperthyroidism is required to prevent the recurrence of paralytic attacks, which can occur in 62% of patients in the first three months after diagnosis [2,9]. Patients should avoid precipitating factors including heavy carbohydrate or sweet intake, excessive activity, emotional stress, and alcohol consumption until thyrotoxicosis is controlled.

TPP should be considered as a differential diagnosis in male patients especially those of Asian descent who present with muscle weakness. Although TPP is more common in Graves' disease, it can occur with any form of thyrotoxicosis including thyroiditis. TPP is also usually associated with hypokalemia but in rare cases, the patient may be normokalemic. Management of TPP is a combination of definitive therapy for hyperthyroidism, correction, and monitoring of serum potassium levels while avoiding precipitating factors to prevent recurrent paralysis.

Conflict of Interest

None declared

Funding

No funding sources 

Author Contributions

All authors have a balanced contribution to this paper

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