Hypercalcaemic encephalopathy as a presenting manifestation of sarcoidosis

Abstract

A 66-year-old woman presented to us with features of encephalopathy with asterixis, preceded by unsteadiness of gait and behavioural abnormalities. On subsequent investigations, hypercalcaemic crisis and compromised renal function were noted. Stepwise approach to determine the cause behind hypercalcaemia with compromised renal function revealed underlying granulomatous disease (sarcoidosis). Later, development of maculopapular rash and subsequent biopsy from the lesion confirmed the diagnosis of sarcoidosis. Her clinical and biochemical parameters improved considerably on initiation of conservative pharmacological therapy.

Background

Hypercalcaemia is a recognised association of sarcoidosis.¹ Renal malfunction in sarcoidosis is seen in approximately 3% of patients with sarcoidosis either due to disrupted calcium metabolism or underlying granulomatous interstitial renal involvement.² Asterixis is an uncommon presenting finding of sarcoidosis. Asterixis is an important clue for diagnosis of hepatic encephalopathy and to some extent, uraemic encephalopathy. Here, hypercalcaemic encephalopathy with asterixis, in a sexagenarian female ultimately unfurled the diagnosis of sarcoidosis with renal failure. This unique presenting manifestation makes this case worthy of presentation.

Case presentation

A 66-year-old married non-diabetic, hypertensive woman of Asian ancestry presented on 29 October 2020 with progressive deterioration in consciousness during the last couple of weeks. One and half months ago, she reported continuous, low-grade fever (temperature: 100°F–101°F) accompanied by night sweats, dry cough, mild dyspnoea, chest pain and generalised myalgia. Conservative management at home led to disappearance of symptoms within 1 week. Three weeks later, she started developing insidious onset, gradually increasing unsteadiness of gait associated with frequent falls. Within a week, she was incapacitated, virtually unable to perform her activities of daily living and was confined to bed. However, while lying on bed, she could still move her limbs. During this period, her relatives also noticed an alteration in her behaviour characterised by impaired comprehension and irrelevant talk followed by withdrawal from the surroundings. Consciousness further deteriorated and finally, 1 week before admission, she slipped into a state of profound unconsciousness with unresponsiveness to painful stimuli. Before hospitalisation, the patient underwent domiciliary treatment under the supervision of a private medical practitioner.

On examination, her Glasgow Coma Score was found to be E4V5M6. Asterixis was noted at both wrist joints. Patient was afebrile with blood pressure of 180/80 mm Hg and pulse of 116 /min. Careful inspection revealed circular, erythematous, maculopapular rashes on back and extensor surface of upper limbs.

Investigations

Laboratory parameters have been summarised in table 1. On admission, analysis of serum electrolytes revealed hypercalcaemia. Renal function test was abnormal with elevated serum creatinine and blood urea nitrogen. Complete haemogram revealed mild anaemia, decreased packed cell volume and increased red cell distribution width. Erythrocyte sedimentation rate was increased. Levels of blood glucose and other serum electrolytes (sodium, potassium, magnesium, chloride, phosphorus), results of hepatic function tests (including prothrombin time and international normalised ratio), results of thyroid function tests, values of C reactive protein and procalcitonin were within normal limits. Serum ammonia level was found to be normal. Further assessment of hypercalcaemia showed an increase in serum 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D; simultaneous decrease in parathormone level and rising level of serum ACE. Results of serum protein electrophoresis and urinary free light chain assay were negative. Cerebrospinal fluid (CSF) analysis was normal. Reports of paired sera (sent for autoimmune encephalitis panel), antinuclear antibody screening (using Hep-2 cells) and Antinuclear Antibody (ANA) profile were negative. CSF culture and PCR assay for JC virus and Epstein-Barr virus revealed no evidence of infection. No acid fast bacilli were detected in sputum and Cartridge-Based Nucleic Acid Amplification Test was negative. She was found to be HIV seronegative. High resolution CT of thorax (figure 1A, B) revealed bilateral hilar adenopathy with perilympahtic and perivascular pulmonary nodules and diffuse emphysematous changes in both lungs. Imaging of abdomen showed no remarkable abnormality except for bilateral marginal increase in renal echogenicity on Ultrasonography (USG) and tiny left renal calculus on CT. Serum parathyroid hormone-related protein (PTH-rP) level was normal. Electroencephalography (EEG) recorded background activity of 5–6 Hz in the posterior head regions, symmetrical and synchronous with intermittent and generalised polymorphic theta-delta slowing suggestive of a diffuse encephalopathy. MRI brain was normal except for periventricular ischaemic changes. Histopathological examination of tissue specimens (figure 2) obtained from cutaneous lesions reported the presence of non-caseating granulomas with occasional multinucleated giant cells in the upper epidermis.

Table 1.

Laboratory parameter details

Laboratory parameters	Results	Reference range
Albumin adjusted serum calcium	13.98 mg/dL	8.5–10.1 mg/dL
Serum albumin	3.4 g/dL	3.4–5 g/dL
Serum creatinine	4.09 mg/dL	0.6–1.2 mg/dL
Blood urea nitrogen (BUN)	42 mg/dL	7–18 mg/dL
Haemoglobin	105 g/L	120-155 g/L
Packed cell volume	32.6%	35.5%–44.9%
Red cell distribution width	15.3%	12.2%–14.5%
Erythrocyte sedimentation rate (ESR)	66 mm/hour	0–30 mm/hour
Serum ammonia	20 µmol/L	11–32 µmol/L
Serum 25 hydroxyvitamin D	32.17 ng/mL	20–30 ng/mL
Serum 1,25 hydroxyvitamin D	23.96 pg/mL	15–20 pg/mL
Parathormone level	4 pg/mL	9.2–44.6 pg/mL
Serum ACE	129.00 units/L	8–65 units/L
Serum parathyroid hormone-related peptide (PTH-rP)	1.5 pmol/L	Considered elevated when >2.5 pmol/L

Figure 1.

(A, B) High-resolution Computed Tomography (HRCT) thorax revealed ‘mediastinal widening with ground glass opacities mainly involving right posterolateral segment’ (black arrows with red outline indicate hilar lymphadenopathy and white arrows with black outline indicate lung parenchymal infiltrates).

Figure 2.

Istopathological findings of cutaneous lesions (black arrow indicates non-caseous granuloma).

Differential diagnosis

1. Hypercalcaemic encephalopathy due to sarcoidosis

   (points in favour of this diagnosis: the clinical presentation, elevated serum calcium level, EEG findings and prompt response to treatment with diuretic and fluid are suggestive of hypercalcaemic encephalopathy. Diagnosis of sarcoidosis³ can be made from the elevated serum ACE levels, bilateral hilar adenopathy with lung field changes on High-resolution Computed Tomography (HRCT) and non-caseating granulomas on skin biopsy. Thus, hypercalcaemia, a common association of sarcoidosis, possibly led to hypercalcaemic encephalopathy).

2. Uraemic encephalopathy (metabolic encephalopathy is a very close differential diagnosis of uraemic encephalopathy. Uraemic encephalopathy is a diagnosis of exclusion with no specific confirmatory test to diagnose it. However, uraemic encephalopathy is an absolute indication to initiate renal replacement therapy (RRT). In our case, marked improvement of encephalopathy coincided with correction of hypercalcaemia and did not require any RRT. Hence, hypercalcaemic encephalopathy seems to be a more likely possibility in this situation. Besides, absence of uraemic symptoms, normal serum phosphorus level and no acute rise in serum urea and creatinine levels, also do not favour the diagnosis of uraemic encephalopathy).

3. Hepatic encephalopathy (normal liver function test including prothrombin time and international normalised ratio and normal serum ammonia level suggested that encephalopathy was not due to hepatic dysfunction).

4. Other metabolic encephalopathies (extensive laboratory workup of possible metabolic disorders revealed no abnormality and thereby excluded encephalopathy due to other metabolic causes).

5. Autoimmune encephalitis (paraneoplastic or non-paraneoplastic) (although contrast study and Positron Emission Tomography-Computed Tomography (PET-CT) could not be conducted in view of elevated serum creatinine level; USG of whole abdomen, CT imaging of thorax and whole abdomen and PTH-rP levels showed no change suggestive of malignancy; autoimmune encephalitis panel was also found to be negative).

6. Hypercalcaemia:

   1. Parathyroid hormone-mediated (PTH-mediated)

   • Hyperparathyroidism: decreased serum PTH levels, normal serum phosphorus levels and normal arterial blood gas in absence of characteristic radiographic findings exclude this possibility.

   • Familial hypocalciuric hypercalcaemia: seems unlikely considering negative family history.

   1. Non-parathormone-mediated (non-PTH-mediated)

   • Malignancy: although contrast study and PET-CT could not be done, normal imaging findings (USG of whole abdomen, CT imaging of thorax and whole abdomen) suggested absence of evidence of malignancy. Serum PTH-rP was done even in absence of any focal lesion on CT chest. Serum PTH-rP value was within the normal range, thereby further excluding the chance of malignancy.

   • Multiple myeloma: both serum protein electrophoresis and urinary free light chain assay were not contributory towards this diagnosis.

   • Vitamin D intoxication: it is usually suspected when serum 25(OH) vitamin D concentration >150 ng/mL. Here, serum 25(OH) vitamin D was 32.17 ng/mL.

   • Endocrine disorders like thyrotoxicosis, primary adrenal insufficiency, pheochromocytoma were ruled out in view of normal thyroid profile and normal serum sodium and potassium levels.

   • Intake of drugs for example, thiazides, vitamin D and vitamin A: there was no history of intake of such drugs.

   • Immobilisation: prior to onset of symptoms, patient was ambulatory. So this possibility stands eliminated.

Treatment

Initially, the patient was administered intravenous normal saline (0.9%) at the rate of 300 mL/hour on first day and urine output at the end of 24 hours was 2200 mL. Intravenous furosemide 40 mg 12 hourly was given for 2 days to overcome the volume overload in background of renal failure. Calcitonin (4 IU/kg) was administered by deep intramuscular injection 12 hourly for 2 days. To overcome hypercalcaemic crisis, intravenous hydrocortisone was administered 100 mg three times per day for 2 days. However, after excluding steroid responsive hypercalcaemia (myeloma, malignancy and vitamin D intoxication) and identifying the exact underlying aetiology, oral steroid (prednisolone 50 mg per day) was administered in association with methotrexate 15 mg weekly and hydroxychloroquine 300 mg per day. After 2 months of combination therapy (to allow methotrexate to initiate its action), prednisolone was gradually tapered at the rate of 5 mg per week. Physiotherapy was initiated when the patient regained consciousness.

Outcome and follow-up

Our patient showed significant improvement in clinical and biochemical parameters on institution of conservative pharmacological therapy. Within 10 days of admission, her serum calcium and serum creatinine level dropped to 10.1 mg/dL and 1.96 mg/dL, respectively. Repeat EEG on 10th day recorded normal background alpha rhythm, responsive to eye-opening without any epileptiform discharge. At the time of discharge, she was alert, conscious, oriented and ambulant without support. Patient has been followed for 8 months until and she has maintained her clinical and biochemical improvement.

Discussion

Hypercalcaemia is a potentially life-threatening and relatively uncommon metabolic derangement with an incidence of 0.17%–2.92% in hospital populations.⁴ Approximately 0.6% of all acute medical admissions can be attributed to hypercalcaemia.⁵ Approximately 90% of all cases of hypercalcaemia is due to malignancy and primary hyperparathyroidism.⁶ Association of hypercalcaemia and granulomatous diseases was first established in 1939 by Harrell and Fisher.⁴ A study carried out by Kuchay et al revealed that 5.3% cases of non-parathyroid hypercalcaemia were due to sarcoidosis.⁴ Hypercalcaemia can be observed in 2%–63% of patients with sarcoidosis.⁷ Thus, it may be concluded that sarcoidosis is a relatively uncommon aetiology of hypercalcaemia. In sarcoidosis, hypercalcaemia occurs due to dysregulated production of calcitriol by activated macrophages in pulmonary alveoli and granulomatous inflammatory sites.

Detection of an elevated serum calcium level on biochemical screen is the most common clinical presentation of hypercalcaemia.⁵ If symptomatic, hypercalcaemia presents with depression, myalgia, arthralgia, renal colic or abdominal pain due to peptic ulcer or constipation.⁵ In our case, hypercalcaemia first unfolded in the form of myalgia, alteration of behaviour, gait changes and impairment of consciousness.

Sarcoidosis is a chronic granulomatous disorder that has myriad of clinical features depending on the organs affected. Lungs are the most common organs involved (90%) followed by lymph nodes (33%), liver (histopathological abnormalities seen in 50%–80% of biopsy specimens), skin (25%), eyes (11%–83%), musculoskeletal system (25%–39%) and endocrine glands.⁸ Nervous system is affected in sarcoidosis in approximately 5%–16% of cases in clinical settings and 15% in pathological studies.⁸ The most common clinical manifestation of neurosarcoidosis is cranial neuropathy (75% of cases) with the seventh nerve being the most commonly affected cranial nerve.⁸ About 50% of neurosarcoidosis patients report brain parenchymal disease, out of which only 5% cases account for encephalopathy.³ The pathogenesis of encephalopathy in sarcoidosis is not clearly understood. The role of hypercalcaemia as a key factor in the development of encephalopathy in sarcoidosis remains relatively unexplored in medical literature. In spite of similar case reports described earlier,⁹ hypercalcaemic encephalopathy as presenting manifestation of sarcoidosis is a rare phenomenon.

Another clinical finding noted in this patient was gait instability. In view of normal deep tendon reflexes, gait instability in our case was probably due to the fact that cerebellum or its connections might have been affected. Although gait changes have been described in the past in sarcoidosis patients,^{10 11} isolated involvement of cerebellar hemispheres in sarcoidosis is extremely rare. Ataxia has been mentioned as a presenting feature of hypercalcaemia in cases of primary hyperparathyroidism¹² and vitamin D intoxication.¹³ However, proper pathogenetic mechanisms have not yet been quite well-explained.

Asterixis is another interesting finding in our patient. This negative myoclonic jerk may be caused by various factors like hepatic encephalopathy, uraemic encephalopathy, respiratory insufficiency and metabolic disturbances (like hypokalaemia and hypomagnesaemia). In our case, asterixis could be due to uraemia. However, its occurrence due to hypercalcaemia cannot be ruled out from the available investigations. Asterixis has been described as a presenting manifestation of hypercalcaemia in cases of prostate adenocarcinoma,¹⁴parathyroid adenoma¹⁵ and sarcoidosis with bilateral pleural effusion.¹⁶ Interestingly, asterixis, a rare presenting manifestation of sarcoidosis, was found in our case.

Patient’s perspective.

Initially I was depressed for my inability to work due to tremulous movement of my hands and unsteadiness while walking. I cannot recall anything regarding my admission and initial hospital stay. Caregiver let me know that I regained consciousness after treatment by a group of consultants and administration of injectable medications. Presently, tremulous movement of my hands has stopped. I can walk independently and perform my daily normal activities. Currently I am on oral medications and am doing fine.

Learning points.

• Among the presence of plethora of neurological manifestations, encephalopathy and asterixis may be the presenting manifestation of sarcoidosis secondary to hypercalcaemia or uraemia.

• Initial symptoms of mild cough, fever or chest discomfort, even if self limiting, must be dealt with caution to get an early clue towards diagnosis.

• Although neurological manifestations of sarcoidosis may greatly mimic demyelinating disorders of the central nervous system, it should be considered in the differential diagnosis of an encephalopathic presentation secondary to electrolyte imbalance or renal failure.

Ethics statements

Patient consent for publication

Next of kin consent obtained.