Hypokalemic periodic paralysis presenting as asymmetric focal flaccid paralysis: A case report and literature review

Abstract

Patients with the most common form of hypokalemic periodic paralysis (HypoKPP) exhibit symmetrical limb weakness. However, few patients present with asymmetric limb weakness. Here, we describe a unique case of HypoKPP presenting as asymmetric focal flaccid paralysis. In addition, a literature review is performed to provide a perspective for clinical management of similar cases. We present a detailed characterization of this rare type of HypoKPP. The initial presentation was right hand weakness, which progressed to bilateral lower limb weakness. Neurological examination showed that the affected muscles were uniquely confined to specific nerve innervation, i.e., right distal median nerve-innervated muscle, right deep peroneal nerve-innervated muscle and left side. The patient's serum level of potassium was lower than normal; the decline of long exercise test (LET) was higher than normal range; neurophysiological assessment revealed low amplitude compound muscle action potential (CMAP) during attack, the CMAP and patient's weakness rapidly returned to normal level after potassium supplementation. Therefore, HypoKPP can be formally diagnosed based on neurological examination, medical history, timely neural electrophysiological examinations and measurement of blood potassium level.

1. Introduction

HypoKPP is caused by mutations in genes encoding skeletal muscle ion channels, primarily calcium channel, and sodium channel in some cases. The mutations cause anomalous gating pore current through ion channels rendering the muscle sarcolemma unable to contract due to failure to generate a muscle action potential leading to flaccid paralysis. In most cases, HypoKPP patients present as acute generalized flaccid paralysis and a few cases manifest as acute focal flaccid paralysis. These clinical symptoms are accompanied by hypokalemia [[1], [2], [3], [4], [5], [6], [7],9]. Genetic testing is recommended as the first diagnostic criteria for HypoKPP. However, for up to 30% patients have no genetic mutations, the diagnosis should be based on clinical presentation, family history, serum potassium levels during attack and LET results [9,10]. The clinical presentation of patients with focal flaccid paralysis HypoKPP varies, and some cases may be misdiagnosed as other diseases [[1], [2], [3], [4], [5], [6], [7]]. Here, we report a case of HypoKPP presenting as asymmetric focal flaccid paralysis and detailed physical examination of nervous system, electrophysiological examination and gene detection result are discussed.

2. Case presentation

A 55-year-old male construction worker was admitted to our hospital due to right hand weakness for 2 days and bilateral lower limb weakness for 1 day. The patient experienced diminished grip strength in his right hand 2 days prior to admission. Although he was unable to hold heavy objects with his right hand, the patient was still able to carry out his daily work. The patient received massage and cupping therapy at a private practice, which only slightly improved his symptoms. However, 1 day prior to admission, the patient experienced new-onset bilateral lower limb weakness. He was unable to walk normally and was admitted to our hospital. Upon examination, he had no notable history of disease but was addicted to carbonated beverages. He reported a high intake of carbonated beverages following work-related fatigue prior to the initial onset. Neurological examinations revealed grade 4/5 strength in his right distal median nerve-innervated muscle, including the flexor digitorum superficialis, flexor digitorum profundus (the second and third finger), abductor pollicis brevis, flexor pollicis longus, flexor pollicis brevis, and opponens pollicis. Moreover, he had grade 3/5 strength in his right deep peroneal nerve-innervated muscle and grade 4/5 strength on his left side, including the tibialis anterior, extensor digitorum longus, extensor digitorum brevis, and extensor hallucis longus. All other muscle groups were normal and no abnormalities were detected in examinations of the sensory system. The bilateral brachoradialis, biceps, knees, and ankle reflexes were all normal, as were the cranial nerves. Clinical myotonia, including grip myotonia and percussion myotonia were not detected. We suspected that the patient may have developed atypical Guillain Barré syndrome (GBS) and performed nerve conduction velocity (NCV) and electromyography (EMG) examinations. NCV was normal in the tibial nerve, femoral nerve, ulnar nerve, radial nerve, and axillary nerve, but motor responses were abnormal in the right peroneal nerve motor (Table 1). All EMG tests results were normal in the corresponding muscles. Routine biochemical parameters on admission revealed a low blood potassium level of 2.83 mmol/L (normal range: 3.5–5.5 mmol/L) but there were no abnormalities in liver and kidney function tests. We opted no to perform a lumbar puncture. Instead, oral and intravenous potassium supplementation were given immediately and no other special treatments were given. In addition, we conducted thyroid function, plasma renin/aldosterone ratios, adrenal contrast-enhanced computed tomography (CT), and urine pH measurement; all findings were normal. The patient denied any similar history of muscle weakness and hereditary diseases. Following the initiation of potassium supplementation, the patient's symptoms improved rapidly. On day 5 of admission, muscle strength had completely returned to normal. A second round of NCV tests were conducted on the same day which confirmed that the indices of right peroneal nerve motor were restored to normal. The first test showed that right median nerve motor and left peroneal nerve motor were within the normal range, but the second CMAP amplitude values of right median nerve motor and left peroneal nerve motor were higher than those of the first test. For the right median nerve motor-abductor pollicis brevis, the value increased from 9.8 to 17.2 (mV) whereas for the peroneal nerve motor (left)-extensor digitorum brevis, it increased from 3.1 to 4.6 (mV). The value increased from 6.3 to 9.6 (mV) in the peroneal nerve motor (left)-tibialis anterior muscle. After ruling out technical reasons and other possible factors, we postulated that the difference was caused by the disease itself. The first NCV tests result was corrected as right median nerve motor and bilateral peroneal nerve motor were abnormal. LET was then conducted with a distal stimulation site over the ulnar nerve at the wrist; the recording was performed in the abductor digiti minimi muscle. The percentage of LET decrease (%) = (greatest amplitude after exercise - the lowest amplitude after exercise)/greatest amplitude after exercise*100, more than 40% reduction after exercise indicates a positive LET result. The specific methodology was described previously by McManis et al. [8]. A 66.32% reduction in the amplitude of post-exercise CMAP was obtained (Fig. 1). We postulated that his muscle weakness condition was triggered by two key factors: heavy physical work and a large intake of carbohydrate. Therefore, common genes associated with HypoKPP (SCN4A, CACNA1S and KCNE3) were explored, and no mutation of any form was detected. The patient met the following diagnostic criteria for HypoKPP [9,10]: (1) a attacks of muscle weakness with documented blood potassium less than 3.5 mmol/L; (2) greater than 3 of 6 clinical or laboratory manifestations: attack duration great than 2 hours, positive triggers (high carbohydrate, rest after heavy physical activity), remission after potassium intake, positive LET result; (3) exclusion of other causes of hypokalemia (no kidney, adrenal, thyroid function related diseases; no renal tubular acidosis; no diuretic and laxative abuse); (4) no myotonia was found clinically or through electromyography; (5) reduced CMAP during attack. Of note, the present case with an older age of onset (55 years old) seemed to not match the HypoKPP diagnostic criteria. Moreover, the presentation of HypoPP changes with age, with younger patients showing episodic paralysis and elderly patients often presenting with more permanent weakness [11]. Although the patient's conscious muscle strength returned to normal, the second NCV examination showed that the CMAP amplitude of bilateral tibialis anterior muscles was not equal, that is, the amplitude of the left side was lower than the right side, suggesting that the right side might have been damaged originally. Therefore, we hypothesized that the patient had a history of damage, but the symptoms were mild and subclinical, hence the patient was not aware of it. In future, we need to perform imaging and muscle histology examination of the patient's muscles to clarify this possibility.

Table 1.

NCV examination results for motor responses. The first NCV was performed on day 1 of admission while the second NCV was performed on day 5 of admission.

Motor nerve conduction studies	Patient values (1st)	Patient values (2nd)	Normal values
Median nerve motor (right) wrist- APB
Amplitude P–P (mV)	9.8	17.2	≥4.0
Conduction Velocity (m/s) - wrist to elbow	57	57	≥49
Peroneal nerve motor (right) ankle- EDB
Amplitude P–P (mV)	1.0	7.2	≥2.0
Conduction Velocity (m/s) - ankle to below the fibular head	47	53	≥44
Peroneal nerve motor (left) ankle- EDB
Amplitude P–P (mV)	3.1	4.6	≥2.0
Conduction Velocity (m/s) - ankle to below the fibular head	50	53	≥44
Peroneal nerve motor (right) the fibular head - TAM
Amplitude P–P (mV)	1.8	12.5	≥3.0
Conduction Velocity (m/s) -below to above the fibular head	53	53	≥44
Peroneal nerve motor (left) the fibular head - TAM
Amplitude P–P (mV)	6.3	9.6	≥3.0
Conduction Velocity (m/s) -below to above the fibular head	58	58	≥44

NCV = nerve conduction velocity; APB = abductor pollicis brevis; EDB = extensor digitorum brevis; TAM = tibialis anterior muscle; Amplitude P–P refers to CMAP amplitudere, it presents distance between negative-going wave peak and following positive-going wave peak.

Fig. 1.

The results and changing trend of LETs in the abductor digiti minimi, A) Actual amplitude change, B) Overall downward trend. LET = long exercise test.

Based on the above findings, a diagnosis of sporadic HypoKPP was made; and the patient was advised to reduce his intake of carbonated beverages.

3. Discussion

In June 2022, we performed a literature review of previous studies identified through a search on the PubMed and EMBASE databases. The search was conducted using the following keywords: “Hypokalemic”, “HYPOKPP”, “hemiplegia”, “laterality”, “triplegia”, “asymmetrical”, “single limb”, “focal”, “unusual” and “atypical”. The search was limited to case reports or letters published in English. We excluded cases involving weakness in the symmetrical limbs or muscle groups or mononeuropathy and cases with symmetric onset progressing to asymmetric damage. However, we included cases with asymmetric onset progressing to symmetrical damage.

The full texts of the selected studies were examined, and seven studies (eight patients) were deemed suitable and included in the final analyses [[1], [2], [3], [4], [5], [6], [7]]. The seven studies included in the final analysis are summarized in Table 2. On the basis of rigorous diagnostic standards [9,10]; the studies cases were divided into HypoKPP, suspected HypoKPP and secondary low serum potassium. Notably, four patients had limb weakness on one side (50%), three patients had single limb weakness (37.5%), and one patient had local muscle weakness (12.5%). Only three patients received NCV/EMG examination (37.5%); none of the patients received LET examination. In most patients, limb weakness were general and there were only vague descriptions of the weakness (87.5%). Thus, we were unable to ascertain whether “limb weakness” involved all muscles or just weakness in muscles innervated by specific nerves. The lack of detailed physical examinations may have led to the misdiagnosis of partial muscle involvement as total limb involvement. Of the seven studies, only two described innervated muscle involvement in detail. Negrotto et al. [2] reported one case with left wrist extension, finger extension and weakness in the interosseous muscle whereas Chui et al. [4] reported a case with weakness in the left thumb. Interestingly, NCV tests in these two cases were normal. These results are significantly different from those of symmetrical HypoKPP [9] and our present case. However, it should be noted that the two existing studies did not mention the specific time that the NCV examinations were carried out. The results of NCV examinations may be normal if not carried out at the specific time of attack/weakness. Alternatively, it is possible that a different mechanism related to asymmetric HypoKPP exist; however, this possibility requires further investigation.

Table 2.

Clinical features and key information for the cases presented.

Cases	Patient characteristics	Sex	Age (years)	Etiology	NCV/EMG	K+ level	Neurological examination	Family history of similar disease	Possible triggers
Katabi A et al.[1] (HypoKPP)	Bilateral leg and left arm weakness	M	40	NA	NA	1.9 mmol/L (normal range: 3.5–5.0mmol/L)	NA	No	History of recent exercise
Negrotto L et al.[2] (secondary low serum potassium)	An isolated mild right brachial paresis, and extend to upper and lower limbs weakness on admission	F	51	Renal tubular acidosis	Normal	2.2 mEq/L (normal range: 3.5–5.0 mEq/L).	1.Onset stage: NA 2.On admission: predominantly proximal grade 2/5	NA	NA
	Left-hand weakness	M	47	Primary hyperaldosteronism	Normal	1.8 mEq/L (normal range: 3.5–5.0 mEq/L).	Weakness of left wrist and finger extensors (grade 2/5 and 3/5, respectively) and “mild weakness of left interosseous muscles”	NA	NA
Lu YT et al.[3] (suspected HypoKPP)	Right arm and leg weakness	M	52	Subclinical corticospinal tract damage hypothesis	NA	1.8 mEq/L (normal range: 3.0–4.8 mEq/L)	Grade 2/5	NA	NA
Chui C et al.[4] (secondary low serum potassium)	“Could not extend or elevate her left thumb”	F	48	Adrenal adenoma	Normal	1.9 mEq/L (normal e range: 3.4–5.0)	NA	No	Frequent exercise in her job

NA = not available; F = female; M = male; NCV = nerve conduction velocity; EMG = electromyography.

Currently, the difference between focal flaccid paralysis and generalized flaccid paralysis HypoKPP cannot be explained. The etiology of focal flaccid paralysis HypoKPP is complex and likely to differ between cases. One possibility is that original hemiplegic basic diseases such as post-stroke hemiparesis and cervical spondylitis may induce hemiplegic limb weakness [3]. In addition, HypoKPP is related to the formation of anomalous gating pore current through the calcium channel/sodium lion channel. Just like the vigorous activity of local muscles in LET test can cause a decrease in focal muscles CMAP [8], vigorous activity of local muscles may cause focal muscles weakness. The present patient worked in a steel bar tying group. His daily task was to tie steel bars tightly with his right hand; often, he had to stand on tiptoe to access high points. The acute onset of some focal flaccid paralysis HypoKPP cases may be misdiagnosed as GBS or cerebrovascular disease. Therefore, a careful diagnosis should be made. In addition, HypoKPP patients with focal flaccid paralysis are at risk of developing generalized flaccid paralysis, just like those with secondary low serum potassium cases [2]. Therefore, rapid identification and appropriate intervention are required. When asymmetric focal flaccid paralysis HypoKPP is considered, the following examinations may provide specific clues to the correct diagnoses: (1) blood potassium; (2) timely and complete NCV tests in cases involving muscle weakness, rather than when the muscle strength has returned to normal; (3) provide potassium supplementation and reexamine if there are abnormal NCV and blood potassium results, and (4) LETs.

Ethics statement

The patient provided informed and signed consent for the publication of this case report.

Production notes

Author contribution statement

All authors listed have significantly contributed to the investigation, development and writing of this article.

Funding statement

This study was supported by not-for-profit medical science research foundation of Guangdonprovince (Reference: B2021293).

Data availability statement

Data included in article/supp. material/referenced in article.

Declaration of interest’s statement

The authors declare no competing interests.