This case report describes a diagnostically challenging case of a middle-aged male admitted with severe hyponatremia, fatigue, and incidentally found to have nephrotic-range proteinuria. Although initially suspected to be primary adrenal insufficiency or SIADH, further testing revealed CASPR2 antibody–associated autoimmune encephalitis along with nephrotic-range proteinuria, probably due to membranous nephropathy. This case highlights the importance of considering a broad differential diagnosis in patients with hyponatremia. It emphasises the need to investigate paraneoplastic and autoimmune causes, even in the presence of subtle or non-obvious neurological symptoms. The patient was successfully treated with pulse steroids and intravenous immunoglobulin (IVIG), and additional renal evaluation is ongoing.
Autoimmune encephalitis (AE) is a group of inflammatory brain disorders often linked to antibodies targeting neuronal surface antigens. One subgroup involves antibodies to the voltage-gated potassium channel (VGKC) complex, including CASPR2 (Contactin-associated protein-like 2), which is strongly associated with limbic encephalitis, neuromyotonia, and Morvan’s syndrome. Hyponatremia, especially due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), may occur before or alongside autoimmune encephalitis and is commonly observed in LGI1 and CASPR2 subtypes. Conversely, nephrotic syndrome-particularly membranous nephropathy—is a well-known autoimmune kidney disease. The occurrence of these two autoimmune conditions together is rare and has not been extensively reported in the literature.
A middle-aged male with no prior medical comorbidities presented to the emergency department with progressive fatigue and generalised weakness over 1 week. He denied headaches, seizures, behavioural changes, fever, vomiting, diarrhoea, or polyuria. No history of fluid restriction, excessive fluid intake, or diuretic use was noted. He was not on any medications except for using complementary and alternative medicines for a skin disorder. He had no rash, joint pain, photosensitivity, or recent travel or toxin exposures.
On general examination, the patient was conscious and oriented but appeared lethargic. Vital signs revealed a blood pressure of 112/76 mmHg, a heart rate of 84 bpm, and the patient was afebrile. Neurological examination showed no focal deficits, with intact cranial nerves and no signs of encephalopathy. Other system examinations revealed that the patient was clinically euvolemic, and cardiovascular, respiratory, and abdominal assessments were unremarkable, with no evidence of peripheral edema. Laboratory assessment demonstrated severe hyponatremia on point-of-care venous blood gas analysis, with sodium <100 mg/dL, chloride 70 mg/dL, bicarbonate 18 mmol/L, and no acid–base imbalance. Initial investigations confirmed a serum sodium of 100 mmol/L, serum osmolality of 230 mOsm/kg, urine osmolality of 260 mOsm/kg, urine sodium of 60 mmol/L, and serum bicarbonate of 18 mmol/L. Serum cortisol was low at 155 nmol/L, while thyroid-stimulating hormone (TSH) was normal at 1.42 µIU/mL. The urine protein-to-creatinine ratio was markedly elevated at approximately 10 g/g, with a reduced serum albumin of 2.2 g/dL. Lipid profile revealed an LDL cholesterol of 165 mg/dL, while renal function tests were within normal limits. Urinalysis showed 4+ proteinuria without hematuria and a bland sediment, and urine microscopy demonstrated no dysmorphic red blood cells or casts.
In view of the severe hyponatremia, 3% sodium chloride was administered immediately for correction, and the patient was admitted to the Intensive Care Unit for further management.
These findings suggested hypotonic euvolemic hyponatremia with inappropriately concentrated urine and renal sodium loss — a classical biochemical profile of SIADH. This also revealed a significantly high Proteinuria, which mandated further evaluation, and the Nephrologist’s opinion was promptly obtained. An autoimmune and Infectious Workup was considered due to severe proteinuria and to evaluate atypical presentations of connective tissue disorders: ANA, dsDNA: negative, C3/C4: Normal, HIV, HBsAg, Anti-HCV: non-reactive. With the possibility of an Endocrine disorder with a low normal range serum cortisol level and presenting with severe hyponatremia, Adrenal insufficiency was considered. Neuroimaging was performed to rule out a pituitary disorder. MRI Brain was done, which was Normal; no abnormalities in the temporal lobes or pituitary.
With all efforts to correct the Serum Sodium level, it was wavering around 120-125 for 3 days. 3% NaCl, Fluid restriction was tried initially, later Tolvaptan was added. The patient required around 30mg of Tolvaptan per day for the next 2 days to maintain Sodium around 125-130mmol/L/L. There was no single diagnosis that fit this presentation, and there was no obvious improvement in the patient’s general condition at 6 days of admission. With keen efforts to examine the patient, the patient showed subtle signs of tremors in both hands, dystonic posturing of limbs and progressive decrease in responsiveness as evidenced by a drop in GCS to 8/15. The neurologist’s opinion was obtained. The neurologist suggested this could be a case of Autoimmune Encephalitis in the background of recent intake of complementary/alternative medications, hyponatremia, and subtle movement disorder, and CSF analysis and an Autoimmune Encephalitis panel was done. With the reports awaiting, the patient was started on IVIg (2gm/kg over 5 days). CSF Analysis done showed Cells: 1 (100% neutrophils), Protein: 30.5 mg/dL, Glucose: 101 mg/dL. These findings in CSF did not suggest any acute CNS infection or overt inflammation. After ruling out infections with a blood culture, IV Pulse Methyl prednisolone was started at 1 gram per day for 5 days. On day 2 of Pulse steroids, an Autoimmune encephalitis panel report was obtained, which revealed CASPR2 Antibody Positive, which confirmed the diagnosis of CASPR2-associated limbic encephalitis.
The following differentials were considered. Autoimmune limbic encephalitis (CASPR2-positive) explains the SIADH, subacute tiredness, and seropositivity. Primary adrenal insufficiency was suspected due to low cortisol, but the absence of hyperkalemia or hypotension made primary disease unlikely. Nephrotic syndrome was also considered, as massive proteinuria, hypoalbuminemia, and hyperlipidemia are classical features. The patient ultimately demonstrated a dual autoimmune picture, likely representing autoimmune encephalitis and concurrent autoimmune glomerular disease, possibly membranous nephropathy.
Given the CASPR2 positivity and unexplained SIADH, the patient was initiated on pulse methylprednisolone 1 g IV daily for 5 days along with intravenous immunoglobulin (IVIG) 2 g/kg administered over 5 days. For the management of severe hyponatremia, fluid restriction was implemented to 750 mL per day, hypertonic saline (3% NaCl) was administered cautiously, and serial serum sodium levels were monitored every 4–6 hours. For the nephrotic syndrome, a renal biopsy was planned, and PLA2R antibodies were sent to confirm membranous nephropathy, which subsequently came back negative.
CASPR2-associated autoimmune encephalitis typically presents with seizures, memory impairment, irritability, and SIADH. However, this case was atypical due to the absence of overt neurologic features, a predominant biochemical picture characterised by hyponatremia, and the coexistence of nephrotic syndrome. SIADH in autoimmune encephalitis is well established in both LGI1 and CASPR2 subtypes. In our patient, CASPR2-associated autoimmune encephalitis was the most plausible unifying diagnosis.
The nephrotic syndrome likely reflected an autoimmune glomerular disease, possibly primary membranous nephropathy, which is also immune-mediated. This case highlights that autoimmune encephalitis can present subtly with non-neurologic signs, such as hyponatremia, and that dual autoimmune diseases can coexist in a single host due to shared immunopathogenic pathways.
This case illustrates a rare, dual presentation of CASPR2-positive autoimmune limbic encephalitis and nephrotic syndrome in a previously healthy young male. The key clinical clue was persistent SIADHtype hyponatremia with subtle neurological signs, which guided the autoimmune work-up. Early immunotherapy with IVIG and steroids was initiated, even in the absence of overt neurologic symptoms. Multidisciplinary evaluation, including nephrology and neurology input, was crucial in managing this case effectively.
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Dr Vignesh A S MBBS DNB General Medicine Resident, Kauvery Hospital, Alwarpet, Chennai.
Dr Venkatraman Karthikeayan MBBS, MD (Gen Med), DM/DNB (Neurology), Fellow (MS & euroinflammatory Disorders, UK), Fellow (Advanced Parkinson Therapy, UK) Senior Consultant Neurologist, Kauvery Hospital, Alwarpet, Chennai.
Dr Sivaram Kannan, MBBS; MD (Gen Medicine); FRCP Clinical Lead & Chief Consultant Physician, Kauvery Hospital, Alwarpet, Chennai.
