Hypernatremia in a Cat with Toxoplasma-Induced Panencephalitis

Introduction

Disturbances of the water metabolism associated with hypernatremia are rare conditions and can be caused by loss of free water, hypotonic water loss, or increased intake of sodium. Dependent on its severity and on the speed of its development, hyperosmolality can be life-threatening. The major regulatory hormone responsible for fluid homeostasis is vasopressin (antidiuretic hormone), which is produced in the hypothalamus and released from the pituitary gland. Vasopressin deficiency results in diabetes insipidus consisting of pure water deficit; a low urine osmolality; and, in the case of reduced water intake hypernatremia, high plasma osmolality and hyperchloremia. This report describes an unusual case of a necrotizing panencephalitis involving the hypothalamus and the pituitary gland, presumably causing diabetes insipidus in a cat.

Case Report

A 12 yr old female neutered Carthusian crossbreed cat weighing 1.8 kg was presented at the Clinic of Small Animals, Freie Universität Berlin, Germany due to a 4 mo history of progressive disorientation and anisocoria. The cat lived indoors for the entire life and had been dewormed and vaccinated at irregular intervals. For the last 3 wk, the cat had been treated for hyperthyroidism, hypertrophic cardiomyopathy, and hypertension with carbimazole, ramipril, and amlodipine. Seven days before presentation, total serum T4 was within the reference range. For the last 5 days, severe lethargy, inappetence, and hypodipsia had been present. At presentation, the cat was in lateral recumbency. The body condition score, which deteriorated during the last 3 wk, was 1/9. Mucous membranes were dry and pale, the capillary refill time was prompt, and rectal temperature was 36.2°C. Auscultation of the heart revealed a systolic heart murmur (grade II/VI, left side, fifth to sixth intercostal space) and a heart rate of 124 beats per min. Pulse quality and respiration pattern were normal. The degree of dehydration was estimated as 5–6%. Systolic blood pressure was 100 mmHg^a Neurological examination revealed an abnormal mental status with stupor. The palpebral reflex was normal; however, the menace response could not be assessed. The pupillary reflexes were normal, but anisocoria was present. Spinal reflexes (femoral nerve, flexor reflexes, carpal extensor) and deep pain sensation were normal. The cat was not able to stand without or with assistance and the proprioceptive reflexes with assistance were absent on all limbs. Based on the neurological examination, a central nervous disorder was suspected. Inflammatory, neoplastic, and metabolic/toxic diseases were considered as the most important differential diagnoses. Hematological examination^b revealed an erythrocytosis and a mild leukocytosis with a mature neutrophilia and lymphopenia, consistent with a stress leukogram (Table 1). Biochemistry^c revealed a severe hypernatremia with a calculated plasma osmolality of 378 mOsm/kg (2 Na [mmol/L], reference range 290–330 mOsm/kg).^1,2 Further findings included hyperchloremia, azotemia, increased liver enzymes, hyperglobulinemia, and hyperglycemia. Due to dehydration, a urine sample could not be obtained either via cystocentesis nor manual expression of the bladder. The clinical findings suggested a prerenal azotemia; however, a renal disease as a primary or additional cause of the azotemia could not be excluded. Serological examination for feline leukemia virus antigen and feline immunodeficiency virus antibodies^d was negative. The radiological examination of the thorax showed cardiomegaly (vertebral heart score 9.5, reference range: 6.7–8.1). Ultrasonographic examination of the abdomen was unremarkable.

Table 1 Laboratory Parameters of a 12 Yr Old Cat with Cerebral Toxoplasmosis and Hypernatremia

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The cat was treated in the intensive care unit. To replace the volume deficit, a crystalloid solution^c (sodium content 140 mmol/L) was administered IV (4.4–5.5 ml/kg/hr). Due to an altered state of consciousness, oral rehydration was not possible. After rehydration, a mixed infusion of a crystalloid solution^e and 5% glucose^f (1:2 ratio) at a rate of 3.3–4.4 ml/kg/hr was given to replace pure water losses. Since the glucose is metabolized, an administration of 5% dextrose solution is equivalent to infusion of water.¹ Vital parameters were measured every hour. After 6 hr, the pulse rate increased to 168 per min, the respiratory rate ranged from 16 to 24 per min, and the blood pressure increased to 140–150 mmHg. Initially, electrolyte concentrations were measured every 4–6 hours. Heating blankets and warming systems^g were used to increase body temperature. The urine osmolality measured the day after admission was 516 mOsm/kg (reference range: 50–3000 mOsm/kg).³ The calculated plasma osmolality was 368 mOsm/kg. Within the following 3 days, hydration status and hypernatremia improved, but mild hyperkalemia was detected (Table 1). The cat was able to lie in sternal recumbency, but was not able to stand. Furthermore, the cat was not stupurous, but disoriented and menace response remained absent. The rectal temperature increased to 37.4°C, but did not return to its reference range throughout treatment. At that point of time, the owners agreed to perform further diagnostics. On day 4, a computer tomography (CT) scan of the brain was performed. General anesthesia was initiated with midazolam^h (0.5 mg/kg IV) and propofolⁱ (3 mg/kg) and maintained with an isoflurane/oxygen mixture after intubation. First, a native CT scan of the cranium was carried out using a multi-slice spiral CT.^j The scan was repeated after administration of 4 ml contrast agent (300 mg J/ml IV).^kk A hypodensity of the brain, especially of the right hemisphere and ventral aspect of the brain, including the hypothalamus and pituitary gland, was present (Figure 1). After discussing the CT findings with the owner, the cat was euthanatized. A complete histopathological examination was performed. Main findings included a severe subacute; granulomatous and necrotizing panencephalitis, involving the hypothalamus and the pituitary gland; and Toxoplasma-typical protozoal cysts (bradyzoites). Only a few tachyzoites were found intralesionally (Figure 2). A further finding was a small (0.6 × 0.4 × 0.3 cm), mixed-type meningioma causing pressure atrophy of the parenchyma in the caudal lobe of the cortex, but without invasive growth or distant metastasis. Due to the small size and the absence of invasive growth, it was unlikely that the meningioma was responsible for clinical signs. Moreover, a thyroid adenoma, a biventricular hypertrophy of the myocardium, and a chronic interstitial nephritis were present.

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Discussion

A marked hypernatremia due to a dysfunction of the hypothalamus and the pituitary gland is described in this case report. In patients with vasopressin deficiency, normovolemia is maintained by compensatory mechanisms (e.g., increased thirst). At presentation, the cat described here had progressed to hypovolemic hypernatremia due to insufficient water intake. To the authors' knowledge, this complication has not yet been reported in cats infected with toxoplasmosis. Toxoplasma gondii is a protozoan that occurs worldwide. It belongs to the Apicomplexa and affects all warm-blooded animals.⁴ Cats and other felines are the sole terminal hosts that produce infectious oocysts via the enteroepithelial cycle. Most cats develop immunity, which prevents clinical signs. However, cats can suffer from latent infection and tissue cysts may be present.⁵ Infection occurs via oral intake of sporulated oocysts, of Toxoplasma-infected tissue, or congenitally.⁶ The way of infection in the cat described here is unclear. Indoor cats are most likely infected by feeding on raw meat.⁶ After oral intake of tissue cysts of infected meat, bradyzoites are released in the gastrointestinal tract where they multiply in the epithelial cells of the small intestines. After schizogony is completed, gamogony gives rise to oocysts, which are excreted with the feces. Oocysts become infectious after having undergone sporulation in the environment. After infection via intake of oocysts, sporozoites are released in the gastrointestinal tract. The sporozoites divide and form tachyzoites, which penetrate the mucosa and affect internal organs. In cats, the liver, kidneys, spleen, musculature, lung, heart, eyes, brain, and spinal cord can be affected.^5–7 Tachyzoites can cause massive tissue damage and necrosis; in immune-competent individuals, tachyzoites form bradyzoites. Bradyzoites divide slowly and cause tissue cyst development and latent Toxoplasma infections. Clinical signs of toxoplasmosis can be caused by primary infection or reactivation of a latent infection. Reactivation occurs secondary to immune-suppression in cats suffering from other diseases.⁸ In the cat presented here, a reactivation of a cerebral toxoplasmosis is likely, since mainly bradyzoites and only a few tachyzoites were present. Infectious agents were not found in any other organs. The exact mechanism of reactivation is not known. Other infectious diseases (feline leukemia virus, feline immunodeficiency virus), drugs (glucocorticoids, ciclosporin), neoplasias, or stress may precede reactivation. In certain cats, triggering factors cannot be detetced.⁶

The most important laboratory finding in this cat was marked hypernatremia. Sodium concentrations and osmolality of the extracellular space are regulated by vasopressin. Vasopressin is a hormone that is produced in the hypothalamus and stored in the caudal lobe of the pituitary gland. If plasma osmolality is increased, vasopressin causes water retention in the kidney due to production of aquaporins. Deviations in plasma osmolality as low as 1–2% cause release of vasopressin.¹ Another stimulus for vasopressin release is hypovolemia.⁹ Hypernatremia can occur with hypo-, hyper-, or normovolemia. Hypovolemic hypernatremia, which is the most common cause for increased serum sodium concentrations, is caused by severe renal or gastrointestinal water losses. In the patient described here, there was no history of vomiting or diarrhea. Renal water loss would be a possible cause and may be confirmed by detection of iso- or hyposthenuric urine. However, initially, urine was not available for analysis. Rarely, hypernatremia is caused by hypodipsia due to a dysfunction of hypothalamic osmoreceptors inhibiting the thirst mechanism.^10,11 Hypodipsic hypernatremia has been described in dogs and cats suffering from intracranial disorders and was a possible contributing pathomechanism in this case. Normovolemic hypernatremia is caused by free water deficits due to diabetes insipidus. Due to a lack of vasopressin or reduced renal response to vasopressin, an adequate concentration of urine is not possible. In normovolemic hypernatremia, pure water is lost. Intracellular water flows to the extracellular compartment leading to a constant arterial blood volume. Thus, the patient is normovolemic, as long as the patient has sufficient water intake. However, dehydration or hypovolemia can develop when water intake is reduced, which was the case in the cat described here. Further potential causes for normovolemic hypernatremia are fever, high environmental temperature, and inadequate access to water.¹ Salt intoxication or the administration of hypertonic sodium solutions or sodium bicarbonate may lead to hypervolemic hypernatremia with hypertension and lung edema. Based on the results of the clinical examination and the low blood pressure, hypervolemic hypernatremia was excluded in this case. Primary hyperaldosteronism as a further cause of hypernatremia typically coincides with severe hypokalemia and, therefore, was unlikely in this cat. The cat described here most likely developed hypernatremia due to vasopressin deficiency and a reduced water intake.

Since the chloride transport is linked to sodium, hyperchloremia was also present. However, the serum chloride level was not as severely increased as the sodium concentration. This might be explained by gastrointestinal losses or a chronic respiratory acidosis leading to a compensatory metabolic alkalosis. However, there was no vomiting or diarrhea in the history of the cat. The respiratory tract was normal based on auscultation and on radiography. Further laboratory abnormalities in this cat included hyperglycemia, azotemia, hyperkalemia, hyperphosphatemia, erythrocytosis, increased liver enzymes, hyperglobulinemia, and relative eosinophilia. Hyperglycemia and the persistent lymphopenia despite chronic antigenic stimulation were indicative for a chronic stress response. The degree of azotemia was most likely underestimated due to severe muscle atrophy and due to hyperthyroidism. The increased phosphorus concentration could be due to prerenal or renal disease. Moreover, it is described that cats with hyperthyroidism have hyperphosphatemia as well.¹² Aldosterone stimulates the reabsorption of sodium and the excretion of potassium in the distal tubules. Hypernatremia inhibits aldosterone secretion, thus reducing sodium reabsorption and increasing the plasma potassium concentration.¹³ Dehydration may have been the cause for the erythrocytosis and might have influenced the degree of hypernatremia. Other differential diagnoses for erythrocytosis, which are not likely in this case, are chronic hypoxia, inappropriate erythropoietin production, and polycythemia vera. Possible differential diagnoses for the increased liver enzymes in the cat described here were inflammatory hepatobiliary diseases, neoplasia, hyperthyroidism, and hypoxia due to heart diseases. The hyperglobulinemia and an eosinophil count in the upper range of normal (relative eosinophilia in a stress situation) were probably related to the toxoplasmosis infection.^6,14 Despite hypovolemia, albumin was not increased. Albumin is a negative acute phase protein; therefore, in inflammatory disease states, serum albumin concentration will decrease. Further explanations for hypoalbuminemia in this case were liver failure and renal or extrarenal losses of albumin.

Hypernatremia causes hyperosmolality of the extracellular volume, which causes shrinking of the cells and subsequent neuronal dysfunction. Acute hypernatremia can cause clinical signs at sodium concentrations of >160 mmol/L. The signs are related to the rapidity of onset of hypernatremia and include lethargy, tremor, seizures, coma, or death.^1,15–17 In the cat of this report, the clinical signs were most likely caused by hyperosmolality and Toxoplasma-induced panencephalitis. Hypernatremia should be treated with caution and close monitoring. A rapid correction of hypernatremia results in neurologic complications. Therefore, plasma sodium concentrations should be reduced at a rate of 0.5–1 mmol/L/hr.¹ In order to decrease the serum sodium concentration, the sodium content of the infusion should be lower compared to the serum sodium concentration of the patient. Therefore, in cases of severe hypernatremia, even a 0.9% sodium chloride solution (sodium content 154 mmol/L) can be used for a gradual lowering of the serum sodium concentration.¹⁸ It is very important to increase the body temperature since, in patients suffering from hypothermia, there is a risk of lung edema when fluids are administered.¹⁹ Vasopressin substitution serves to reduce water loss and is described for the treatment of normovolemic hypernatremia.^20–22 In a case study of a dog suffering from lymphosarcoma of the central nervous system, treatment with desmopressin caused significant reduction of sodium concentrations.²² As for the cat described here, there was no examination of impairment of other hypothalamic/pituitary gland functions, such as hypocortisolism or growth hormone deficiency. Hypothermia, which persisted despite warming, could have been related to a dysfunction of the hypothalamus, the location of the temperature regulation center.¹⁹

Conclusion

Hypernatremia due to different pathophysiological mechanisms results in a rise in plasma osmolality. Dependent on its severity and on the speed of its development, hyperosmolality can be life-threatening. Hypernatremia may be caused by central nervous diseases.

The authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors for the preparation of this case report. The authors do not have any potential conflicts of interest to declare.