To the Editor: Primary periodic paralyzes (PP) are autosomal dominant disorders of ion-channel dysfunction characterized by episodic flaccid weakness secondary to abnormal sarcolemmal excitability. Membrane destabilization due to involvement of Na,K-ATPase has been one of the hypothesis for bipolar disorders, and the therapeutic effect of lithium has been linked to it. We report a case of bipolar disorder (BD) co-occurring with periodic paralysis and response to lithium treatment.

Classically, PP is classified as hyperkalaemic (HyperPP) or hypokalaemic (HypoPP), and Andersen-Tawil syndrome (ATS) is characterized by the triad of periodic paralysis, skeletal anomalies, and ventricular ectopics caused by missense mutations or small deletions in potassium channel (KCNJ2), resulting in destabilization of the resting membrane potential in muscle, heart, and brain.(1,2) Bipolar affective disorder is a common, chronic illness, with severe disability. Despite the significant disability of BD, precise knowledge concerning its etiology and pathophysiology is lacking. However, there is some evidence that membrane destabilization plays a significant role in BD. To our knowledge, this is the first time a case with co-occurrence of both these disorders is being reported.

“Ms. A,” age 26, presented with a 2-year illness with episodic exacerbations characterized by pervasive irritability, overactivity, and overtalkativenesss, associated with poor occupational functioning and partial response to valproate, quetiapine, and olanzapine. For 2 years after the onset of mood symptoms, Ms. A had episodes of abrupt-onset, generalized weakness of all limbs, lasting for 30 minutes, with spontaneous resolution and no associated loss of consciousness. These episodes of weakness were present during the exacerbation of affective symptoms. Family history was not contributory. The patient had a history of low birth weight, mild delay in milestones, and poor scholastic performance. On physical examination, she had anomalies that included hypertelorism; flat nasal bridge; low-set ears; ill-formed auricular cartilage, with adherent ears; high arched palate; micrognathia; clinodactyly; and short stature. During her hospital stay, Ms. A had two episodes characterized by abrupt-onset, generalized hypotonia; grade 2 power in all limbs, with absent reflexes; bilateral flexor-plantar response, and normal sensorium. Both episodes lasted for less than 1 hour, and the second episode improved after potassium supplementation. Mental status examination during the inpatient stay revealed increased psychomotor activity, increased speech output, pervasive irritable mood, and impaired concentration, with no delusions or hallucinations. Serum potassium level level during the first episode of weakness was not available; however, during the second episode, it was 5.1 meq/liter. Serum magnesium, calcium, renal and liver function tests, and thyroid profile were within normal limits, and urine for myoglobin was negative. ECG interval was normal (QTc: 0.36 seconds), and there were no ventricular ectopics. The brain MRI was within normal limits. IQ testing revealed an IQ of 57.

The patient was diagnosed with bipolar affective disorder with current episode mania without psychotic symptoms (ICD-10). The impression was periodic paralysis, with which the neurology team in the hospital concurred. She was started on olanzapine 20 mg, to which there was partial response. Lithium carbonate was added, at 900 mg, and increased to 1,050 mg to reach an adequate level (0.8meq/liter). Since the start of treatment with lithium, the episodes of weakness have not recurred, and the patient showed significant response over 3 weeks. At 4-month follow-up, there was no recurrence of episodes of weakness, and significant improvement in mood symptoms was noted.

ATS is characterized by the triad of PP, skeletal anomalies, and ventricular ectopy.^1,2 ATS is caused by missense mutations or small deletions in KCNJ2 gene on chromosome 17q23.1, encoding the inwardly-rectifying K channel, Kir 2.1 in approximately two-thirds of the affected individuals. The gene is expressed in the skeletal muscle, heart, and brain, and has a major role in setting and stabilizing the resting membrane potential. The mechanism for weakness in periodic paralysis is not understood.

The major models for pathophysiology of BD can generally be divided into two general categories: 1) dendritic or postsynaptic models that focus on the function of G proteins, and the second-messengers, Ca and inositol triphosphate (IP3); and 2) the axonal or presynaptic models that focus on membrane pumps and ion fluxes. These models are not necessarily mutually exclusive, and may even represent different manifestations of the same pathophysiological processes. Investigations into the pathophysiology of BD have consistently revealed altered homeostasis of biologically-active alkali and alkaline earth metals, along with alterations in neuronal excitability and activity. There have been studies supporting the notion that a primary or secondary dysfunction of Na, K-ATPase plays a predisposing or more direct etiological role in bipolar illness. Specifically, there may be a reduction in Na, K-ATPase activity that can lead to both mania and depression by increasing membrane excitability and decreasing neurotransmitter release, respectively.³

The above case illustrates comorbid BD with Andersen-Tawil syndrome (ATS), which included nonprogressive periodic weakness and the typical ATS facies. Although ECG did not show any ventricular ectopics, and QTc interval was normal, two of the three criteria are sufficient to make a diagnosis of ATS.⁴ The episodes of intermittent weakness were mainly during exacerbation of manic symptoms. The variability in ATS presentation in the above case may be due to the absence of a family history of periodic paralysis. The episodic weakness seen in affected individuals with ATS has been associated with normal, elevated, but, most commonly, reduced serum potassium levels.^1,2 Muscle biopsy changes are nonspecific in the ATS. Investigations did not reveal secondary causes of periodic paralysis, and patient had a clinical response to the lithium-and-olanzapine combination with no recurrence of weakness.

There may be a common pathophysiology involving membrane destabilization in both BD and primary periodic paralysis. Lithium therapy has already been proposed in various forms of familial periodic paralysis like hypokalemic, hyperkalemic, and hypermagnesemic paralysis, with varying results.^5–8 Also, lithium has an important role in the clinical management of BD, and one of the mechanisms by which lithium works in this disorder is postulated to be through regulation of cell-membrane ATPases.⁹

The above case had clinical manifestations of BD as well as primary periodic paralysis (ATS). To our knowledge, this the first report of a patient with both the disorders responding to lithium. The possible benefits of lithium could be due to the correction of the underlying common pathophysiology. The possible similar pathogenesis of membrane destabilization and response to lithium may throw light on the pathophysiology of mood disorders.