Sjögren’s syndrome (SS) is a systemic autoimmune disorder primarily characterized by lymphocytic infiltration and progressive destruction of the exocrine glands, particularly the salivary and lacrimal glands, resulting in classic symptoms of xerostomia and xerophthalmia [1]. It can occur as a standalone condition, referred to as primary Sjögren’s syndrome (pSS), or in association with other autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, where it is classified as secondary SS (sSS) [2].

The prevalence of SS varies depending on diagnostic criteria but predominantly affects females, with a female-to-male ratio of up to 20:1, and peak incidence occurring in the fourth and fifth decades of life [3]. In addition to exocrine dysfunction, SS often presents with systemic manifestations involving the joints, lungs, skin, kidneys, and nervous system, reflecting its multi-organ autoimmune nature [4,5]. Among renal manifestations, distal renal tubular acidosis (RTA) is a notable but underrecognized complication, attributed to autoimmune-mediated tubulointerstitial nephritis. It results in impaired hydrogen ion excretion in the distal nephron, leading to non-anion gap metabolic acidosis, hypokalemia, and nephrocalcinosis [6].

Hypokalemic paralysis due to RTA can be a primary presentation, especially in patients without overt sicca symptoms, thereby complicating and delaying diagnosis. Furthermore, rare but severe neurological complications, including sensory neuropathy, encephalopathy, osmotic demyelination, and seizures, have been reported in SS and are often attributed to either direct autoimmune CNS involvement or secondary metabolic derangements [7,8]. Central nervous system involvement, while less frequent, can mimic other neurological disorders and requires a high index of suspicion for early detection and management [9].fig 1

Fig 1: pathophysiology of SS

Accurate diagnosis of SS relies on a combination of clinical features and immunological markers, particularly anti-Ro/SSA and anti-La/SSB antibodies, which are present in a significant proportion of cases [3]. Salivary gland biopsy and tests such as the Schirmer test or salivary gland ultrasound further support the diagnosis [10]. In women of reproductive age, SS also raises concerns about fetal complications due to transplacental passage of anti-SSA/SSB antibodies, which can result in congenital heart block.

This case series describes three young female patients who presented with neurological symptoms secondary to hypokalemia due to distal RTA, ultimately diagnosed as pSS. One case also demonstrated metabolic encephalopathy with MRI-confirmed osmotic demyelination. Through this report, we aim to emphasize the importance of considering autoimmune etiologies like SS in patients presenting with unexplained hypokalemic paralysis or encephalopathy, especially in the absence of classical glandular symptoms.

Case 1: Sjögren’s Syndrome with Distal RTA in Pregnancy

A 25-year-old gravida 3 para 1 female at 6 months of gestation presented with acute onset bilateral lower limb weakness, neck muscle weakness, and a history of fall at home. She denied symptoms of vomiting, seizures, loss of consciousness, or visual changes. Notably, she reported multiple dental caries over the preceding six months. She had no prior medical history of diabetes, hypertension, tuberculosis, or autoimmune disorders.

On examination, vital signs were within normal limits. Neurologically, the patient was conscious and oriented, but motor examination revealed decreased tone and diminished power (MRC grade 2/5) in both lower limbs. Deep tendon reflexes were absent in the lower limbs, with preserved sensation.

Initial investigations revealed a non-anion gap metabolic acidosis with severe hypokalemia (serum potassium 2.2 mEq/L), urine pH of 8, and a positive urine anion gap. Autoimmune screening returned a positive ANA with speckled pattern at 1:80 titer, and elevated SSA/Ro and SSB/La antibodies, confirming autoimmune etiology. Obstetric ultrasound and fetal echocardiography were normal.

The clinical presentation was consistent with distal (type I) renal tubular acidosis (RTA) secondary to primary Sjögren’s syndrome (pSS). Hypokalemic paralysis is a known complication of distal RTA in autoimmune diseases like SS . Though sicca symptoms were absent, subclinical salivary gland involvement is not uncommon in pSS. Early diagnosis in pregnancy is critical to mitigate risks of fetal heart block due to transplacental passage of maternal autoantibodies.

The patient responded well to intravenous potassium chloride supplementation, followed by oral potassium citrate and sodium bicarbonate. Muscle strength gradually improved.

Case 2: Classical Sicca Syndrome with Hypokalemic Paralysis

A 42-year-old female presented with two-day history of progressive bilateral lower limb weakness along with dryness of mouth and eyes. She denied any systemic illness or prior autoimmune diagnosis.

Clinical examination revealed lower limb areflexia and profound weakness (MRC grade 0/5), while upper limbs remained unaffected. Sensory functions were preserved.

Laboratory investigations showed serum potassium of 2.0 mEq/L and bicarbonate of 15 mmol/L. Arterial blood gas revealed a pH of 7.02 and a low serum anion gap of 7. Urinary pH was elevated, confirming distal RTA. Autoimmune panel showed ANA positivity and elevated anti-SSA and anti-SSB antibodies. Schirmer’s test was positive for dry eyes.

The diagnosis of primary Sjögren’s syndrome with renal involvement was confirmed. Distal RTA in SS is believed to occur due to autoimmune tubulointerstitial nephritis impairing hydrogen ion secretion in the distal nephron. This case exemplifies classic exocrine and renal features of SS and highlights the underrecognized presentation of SS with electrolyte disturbances leading to neuromuscular symptoms.

Potassium correction led to significant clinical recovery, confirming reversibility of the paralysis once the biochemical imbalance was corrected.

Case 3: Sjögren’s Syndrome with Distal RTA and Metabolic Encephalopathy

A 21-year-old female presented with fever, progressive quadriparesis, slurred speech, and altered mental status over 8 days. She had been previously hospitalized but was referred for worsening neurological symptoms.

Examination revealed profound weakness (MRC grade 2/5), hypotonia in all four limbs, and global areflexia. The patient developed a generalized tonic-clonic seizure during admission. MRI of the brain demonstrated restricted diffusion in the centrum semiovale and bilateral white matter, suggestive of osmotic demyelination.

Initial labs showed serum sodium of 165 mEq/L, potassium 2.6 mEq/L, bicarbonate 13.3 mmol/L, and a pH of 7.34. Urine pH was 7 with a positive urine anion gap. Autoimmune work-up was strongly positive: ANA 1:100 with SSA and SSB antibodies elevated. Renal ultrasound revealed bilateral nephrocalcinosis.

The metabolic encephalopathy was attributed to rapid sodium correction during an earlier hospitalization. Concurrent distal RTA and neurological symptoms pointed toward pSS with CNS involvement. While central nervous system manifestations are rare in SS, they are increasingly reported, including encephalitis, osmotic demyelination, and seizures.

The patient required ventilatory support and aggressive electrolyte management. Gradual neurological improvement was noted over the following week.

Sjögren’s syndrome (SS) is a complex autoimmune disease with a broad clinical spectrum that extends beyond exocrine gland dysfunction to include multiple systemic manifestations. Although the classical presentation includes xerostomia and xerophthalmia, as seen in our second case, many patients may initially present with extraglandular features such as renal tubular dysfunction or neurological disturbances, which can delay diagnosis and appropriate treatment [11].

In all three cases presented, the unifying feature was distal renal tubular acidosis (RTA), leading to severe hypokalemia and neuromuscular symptoms. Distal RTA in SS results from autoimmune tubulointerstitial nephritis causing impaired acidification in the distal nephron. This leads to non-anion gap metabolic acidosis and electrolyte abnormalities, particularly hypokalemia, which can manifest as muscle weakness, areflexia, and even quadriparesis, mimicking neurological disorders [12]. In our first and second cases, the patients presented with flaccid paralysis and absent lower limb reflexes—clinical findings that warranted immediate electrolyte evaluation and autoimmune screening.

Renal involvement in SS is relatively underrecognized, occurring in approximately 4–10% of patients, with distal RTA being the most frequent renal manifestation [13]. While proteinuria or impaired glomerular filtration may also occur, they are less frequent. Renal biopsy, although not performed in our cases, typically shows tubulointerstitial lymphocytic infiltration consistent with autoimmune nephritis [14].

The neurological manifestations in SS can be diverse, affecting both the peripheral and central nervous systems. Peripheral neuropathy, particularly sensory axonal neuropathy, is among the most frequent extraglandular features, found in up to 20–25% of patients [11]. However, central nervous system (CNS) involvement—such as encephalitis, osmotic demyelination syndrome (ODS), and seizures—though rare, has been increasingly documented [15]. In our third case, a young woman developed seizures and MRI findings suggestive of metabolic leukoencephalopathy after rapid correction of hyponatremia, indicative of ODS. While the condition was likely iatrogenic, her underlying autoimmune state and concurrent hypokalemia may have exacerbated neuronal vulnerability [16].

This reinforces the notion that SS patients, particularly those with electrolyte imbalances, are at risk of severe CNS complications. Early identification of metabolic and autoimmune etiologies is critical for preventing irreversible damage.

Another unique aspect of the first case was pregnancy in an undiagnosed SS patient. SS in pregnancy carries fetal risks due to transplacental passage of anti-Ro (SSA) and anti-La (SSB) antibodies. These can lead to congenital heart block, neonatal lupus, and even fetal demise. Screening for these antibodies is recommended in all pregnant women with suspected or confirmed SS, and fetal echocardiographic monitoring is critical [17]. Fortunately, in this case, both fetal and neonatal echocardiography were normal.

Diagnostic work-up in all three patients included positive antinuclear antibodies (ANA) with high titers and speckled nuclear fluorescence, along with strongly positive anti-Ro/SSA and anti-La/SSB antibodies—hallmarks of pSS [11,18]. Notably, not all patients reported sicca symptoms, further emphasizing the heterogeneity of SS. Studies have shown that serological and immunological markers may precede overt glandular symptoms, and thus, patients presenting with unexplained renal or neurological manifestations must be evaluated for SS even in the absence of dryness [19].

Salivary gland ultrasonography, although not used in our cases, is a useful non-invasive adjunct in SS diagnosis and has been shown to correlate with disease activity [20]. It could potentially help stratify patients with atypical presentations and provide supportive evidence alongside serological and histopathological findings.

Timely correction of hypokalemia remains the mainstay in managing acute neuromuscular symptoms of distal RTA. All three patients improved neurologically following appropriate potassium replacement, highlighting the reversible nature of these manifestations when promptly addressed. However, long-term management should include disease-modifying therapies, such as hydroxychloroquine, and in cases with systemic involvement, immunosuppressants or biologics may be warranted [13].

In summary, this case series highlights the diverse and often non-classical presentations of SS, with all patients lacking full-blown sicca symptoms at onset. Neurological involvement and renal tubular acidosis were initial red flags, which guided diagnostic testing and helped avoid misdiagnosis. Awareness among clinicians regarding these atypical presentations is crucial, particularly in young females presenting with unexplained hypokalemic paralysis or neurological symptoms.

Key Learning Points

• Distal RTA can be the first clinical manifestation of pSS and must be considered in any case of unexplained hypokalemia with paralysis.
• CNS involvement, including osmotic demyelination, is a possible but serious complication in SS patients and may arise from secondary metabolic derangements.
• Autoimmune work-up, particularly ANA and anti-SSA/SSB antibodies, should be considered even in the absence of classic glandular symptoms.
• Pregnant women with undiagnosed SS are at fetal risk due to autoantibody transmission, necessitating echocardiographic monitoring.
• Multidisciplinary evaluation is essential for timely diagnosis and prevention of long-term complications in SS patients.

This case series underscores the importance of recognizing Sjögren’s syndrome (SS) as a systemic autoimmune condition that can present beyond classical sicca symptoms. All three patients exhibited distal renal tubular acidosis (RTA) with severe hypokalemic paralysis, a rare but well-documented extraglandular manifestation of SS. One patient further developed metabolic encephalopathy with osmotic demyelination, emphasizing the potential neurological complications arising from electrolyte imbalances and autoimmune activity.

The absence of overt glandular symptoms in two patients illustrates that subclinical or atypical presentations are not uncommon and may lead to delayed diagnosis if autoimmune screening is not considered early. In such cases, anti-SSA and anti-SSB antibodies, along with acid-base and urinary evaluations, are critical diagnostic tools. Moreover, special attention is required in pregnant women, as maternal autoantibodies can affect fetal cardiac conduction.

Prompt identification and correction of biochemical abnormalities can lead to complete neurological recovery. However, long-term management requires immunological assessment and multidisciplinary follow-up to prevent disease progression. Clinicians must maintain a high index of suspicion for SS in patients with unexplained RTA or neurological symptoms, especially among young women.

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