Hyatrogenic Extrapontine Myelinolysis in Central Diabetes Insipidus: Are Cyclosporine and 1-Desamino-8-D-Arginine Vasopressin Harmful in Association?

Mohamad Maghnie, Eugenio Genovese, Stefan Lundin, Federico Bonetti and Maurizio Aricò

Departments of Pediatrics (M.M., F.B., M.A.), Radiology (E.G.), University of Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy; Department of Clinical Pharmacology (S.L.), Lund University Hospital, Lund, Sweden

Address all correspondence and requests for reprints to: Mohamad Maghnie, Department of Pediatrics, University of Pavia, IRCCS Policlinico S.Matteo, 27100 Pavia. Italy. E-mail aricom{at}ipv36.unipv.it


    Introduction
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 Introduction
 DDAVP kinetics
 Differential diagnosis and...
 References
 
PATIENT C.D. was diagnosed at 5 months as having Langerhans’ cell histiocytosis (LCH) affecting bone, skin, and lung, lymphadenomegaly, and hepatosplenomegaly. She was repeatedly treated with chemotherapy, including vinblastine, methotrexate, cyclophosphamide, steroids, and etoposide. At 3.5 yr she developed central diabetes insipidus (DI) during LCH reactivation and received etoposide up to 5.85 g. At 9.3 yr acute promyelocytic leukemia was diagnosed. Complete remission was obtained with chemotherapy, and the child was sent to our department for consolidation with an histocompatibility leukocyte antigen-matched bone marrow transplantation (BMT). She had an untreated marked growth retardation (115 cm, < -3 SD) and very low weight (16.5 kg, < -3 SD). Endocrine evaluation revealed total GH deficiency after two stimuli and a peak GH response to GHRH of 5.6 µg/L. Morning and peak cortisol values after ACTH were normal; thyroid function was normal, and peak TSH response to TRH was 7.5 IU/L. She was on intranasal 1-desamino-8-D-arginine vasopressin (DDAVP) treatment (2.5 µg, twice daily) with good control of DI and normal natremia. Pretransplant brain magnetic resonance (MR) imaging was normal except for a small anterior pituitary and absent posterior pituitary signal compatible with lesional central DI (1). In October 1992, following a conditioning regimen based on Busulfan (4 mg/kg, days -7 to -3), cyclophosphamide (50 mg/kg, days -3 and -2), and Melphalan (140 mg/m2, day -1), she underwent BMT from her histocompatibility leukocyte antigen-matched brother. On day -1, cyclosporine (1.5 mg/kg per day iv) was started together with hyperhydration regimen (3000 mL/m2). Because of unexpectedly diminished request, DDAVP was shifted from intranasal to oral administration and progressively reduced to a minimal dose of 50 µg/daily according to water balance. On day +9 after BMT, she developed mild cutaneous and gastrointestinal graft-vs-host-disease (GVHD). On day +19, because of extremely limited food intake and reduction of muscle mass, she was put on parenteral nutrition. On day +22, she developed confusion, headache, vertigo, nystagmus, dysartria, neck muscle hypotonia, and respiratory distress. Laboratory data including severe hyponatremia (134 mmol/L in the morning, dropping to 125 and then to 118 mmol/L within hours), and plasma hyposmolality (230 mOsm/kg) with impaired water excretion were compatible with what is usually observed in the course of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Fluid intake was restricted; 3% hypertonic saline was infused for 2 h together with furosemide. This led to correction of hyponatremia (127 mmol/L) within 3 h with clinical improvement. Twelve hours later natremia was found to be 146 mmol/L. DDAVP therapy was reduced on day +23 to 25 µg/day based on low urine output; water intake was restricted. On day +24 she had a new episode characterized by the same clinical symptoms, with a rapid drop of natremia from 146–122 mmol/L in a few hours. During the following days her clinical condition worsened, despite persistent water intake restriction. The DDAVP dose was further reduced to 15 µg every 30–36 h with good control of water balance. On day +28 cyclosporine therapy could be withdrawn, and DDAVP dosage was unexpectedly and progressively increased; it was then shifted to intranasal administration until the previous dosage was reached (2.5 µg twice daily). Cerebrospinal fluid was repeatedly negative for chemical examination and bacterial isolates. Funduscopy was negative. MR imaging on day +24 revealed small periventricular white matter images of hyperintensity punctate lesions in T2-weighted images; the pituitary was small, and the posterior pituitary bright signal was not evident (Fig. 1Go). Follow-up MR evaluation on day +31 showed that such images were superimposable in the supratentorial area; they were less evident and less widespread in the infratentorial area. The MR brain appearance was explained as a combination of edema and demyelination.



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Figure 1. Coronal sections: Day 24 (A), Increased subarachnoid spaces and deep cortical sulci (white arrows); T2-weighted periventricular white matter hyperintensity puctate lesions (arrowheads); normal quadrigeminal cistern and cerebellum (black arrow). Month 44 (B), Disappearance of area of hyperintensity, severe cerebral and cerebellar atrophy, abnormal enlargement of quadrigeminal cistern (asterisk). Sagittal sections: Day 0 (C), Normal 4th ventricle (short arrow), quadrigeminal cistern and cerebellum (long arrow), small anterior pituitary (short arrow), and absent posterior pituitary hyperintensity (black arrow). Month 44 (D), Severe cerebral atrophy with enlarged subarachnoid spaces and 4th ventricle (short arrow), quadrigeminal cistern and cerebellum atrophy (long arrow), and pituitary atrophy (black arrow).

 
The child progressively improved up to complete healing of the acute neurological alterations. Four months later, after reintroduction of cyclosporine for intestinal and cutaneous GVHD, her DDAVP request was minimal and returned to 2.5 µg twice daily after cyclosporine withdrawal. At the time of this report, 46 months after BMT, the child is doing well with no evidence of residual leukemia or LCH and good control of DI; recombinant human GH therapy was started at the age of 10 yr at the dose of 15 IU/m2 per week sc, leading to growth velocity increase to 9.8 cm during the first year of treatment. At the last examination, thyroid and adrenal function were normal, whereas hypergonadotropic hypogonadism secondary to ovarian drug toxicity was documented. She attends school and shows minor attention deficit with cerebellar impairment. Current MR evaluation showed severe cerebral, cerebellar, and pituitary atrophy (Fig. 1Go).


    DDAVP kinetics
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 Introduction
 DDAVP kinetics
 Differential diagnosis and...
 References
 
Plasma levels of DDAVP were determined on day +25, before and after DDAVP 15 µg given orally 30 h after the last administration. Blood samples were collected (5 ml) at hours 0, 1, 2, 5, 8, and 24 in tubes containing trasylol 125 (L + EDTA 3 mg and frozen at -20 C until used. DDAVP level was determined as described elsewhere (2). Plasma DDAVP levels were: hour 0 at 0830 h, 51.5 pmol/L; hour +1, 140.5 pmol/L; hour +2, 171.2 pmol/L; hour +5, 163.8 pmol/L; hour +8, 80.3 pmol/L; and hour +24, 76.5 pmol/L.


    Differential diagnosis and literature review
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 Introduction
 DDAVP kinetics
 Differential diagnosis and...
 References
 
This child with central DI, successfully treated with intranasal DDAVP for several years, suffered life-threatening neurological disorders in the course of BMT, which was necessary for her etoposide-associated secondary leukemia (3). Clinical symptoms were suggestive of cerebral infection, drug toxicity, or vascular damage. Despite severe immune suppression, she was not febrile and had no evidence of systemic infection; blood and cerebrospinal fluid examination and culture were repeatedly negative. Cyclosporine-induced neurotoxicity (4) was unlikely because of therapeutic plasma levels and absence of sign of renal toxicity. Stroke-like causes remained possible in the light of respiratory distress. Emergency biochemical screening, however, showed acute hyponatremia. Symptoms such as headache, nausea, vomiting, irritability, restlessness, lethargy, and confusion have been reported in association with sudden drops of natremia, leading to generalized metabolic encephalopathy (5, 6, 7). The clinical picture, including respiratory difficulties and acute healing within hours, appeared compatible with this diagnosis. Recurrence of symptoms with hyponatremia confirmed this causal association. Because the patient had central DI, hyponatremia caused by SIADH was unlikely. Fluid imbalance leading to frequent readjustment of the DDAVP dosage appeared suggestive for a DDAVP-dependent, SIADH-like condition. This was confirmed by DDAVP pharmacokinetic determined on day +25, showing values greatly exceeding the maximum reference reported levels of <20 pmol/L at 71.4 min after 200 µg po (8). Although the mechanism leading to such DDAVP accumulation under a very low dose is not clear, the close temporal relationship between cyclosporine administration and fluid imbalance were suggestive of pathogenic connection. This hypothesis is supported by evidence of 1) very high level of DDAVP during cyclosporine treatment; 2) normal requirement after cyclosporine withdrawal; and 3) minimal requests for DDAVP after cyclosporine reintroduction for GVHD a few months later. Antidiuretic effect of cyclosporine in the absence of high arginine vasopressin plasma levels may be an additional or enhancing mechanism (9).

Management of hyponatremia in this case was suboptimal. Furosemide, 3% hypertonic saline infusion, and minimal water replacement were followed by an increase in serum sodium level of 28 mmol/L within 12 h after the first episode and 24 mmol/L within 24 h after the second episode. Excessive circulating DDAVP caused by drug interaction, malnutrition, and parenteral nutrition might have concurred to impair sodium control. Because renal flow, glomerular filtration, and extracellular fluid are also GH-dependent, in our untreated patient the lack of GH effects on the renal function, the renin-angiotensin system, and the atrial natriuretic peptide (10, 11) may have contributed to difficulty in managing water homeostasis. Hypertonic saline infusion at the usually recommended doses might be less safe, whereas receiving multidrug therapy and DDAVP, which ß half-lives appears greatly longer. Use of less concentrated solution or brief saline infusion with frequent monitoring of serum sodium is essential in such cases.

Imaging findings of symmetrical, multifocal brain demyelination after the two episodes of hyponatremia supported the diagnosis of extrapontine myelinolysis (12). Although gradual correction of the sodium deficit usually reverses the symptoms without any neurological sequelae, excessively rapid correction may account for osmotic brain myelinolysis. This rare condition, usually reported in adults with malnutrition, alcoholism, or advanced liver disease, is responsible for severe encephalopathy in the few survivors (11, 13). Cases in children are exceptional, are usually related to hyponatremia following infusion of hypotonic solution or to SIADH (14), and the incidence of permanent or fatal brain damage is much higher (14, 15). In the present case neurological symptoms might have been triggered by sudden hyponatremia, whereas demyelination probably represents the end result of its rapid correction during the first episode. Following initial improvement, the clinical picture worsened on a second episode of less severe hyponatremia. Whether this was caused by the cumulative effect of the two episodes, to rapid correction, or to associated malnutrition responsible for exhaustion of rapid mechanisms protecting against brain edema (interstitial hydrostatic pressure, osmotic loss of water, and loss of hydrogenic osmolites) (16) is hard to define.

MR follow-up evidence of cerebral, cerebellar, and pituitary atrophy could depend on osmotic demyelination but also on postanoxic encephalopathy as an additional pathogenic mechanism observed in our case during acute respiratory distress. The combination of systemic hypoxemia and hyponatremia is reported to be far more deleterious than is either factor alone (6, 14), because hypoxemia impairs brain adaptation to hyponatremia. Hyponatremia is also reported as responsible for decreased cerebral blood flow (13). Moreover, high levels of vasopressin may also impair vascular brain adaptation to hyponatremia (17, 18). Whether a reduced cardiac performance in our patient with long-standing severe GH deficiency may have worsened hypoxemia remains an interesting subject of speculation.

In conclusion, management of DI may be extremely difficult when the patient undergoes intensive therapy such as that requested during BMT. Life-threatening complications may occur following interference of multidrug therapy with DDAVP metabolism. We suggest that cyclosporine, like other known drugs, may alter kidney water excretion through slow metabolism/clearance with increased DDAVP bioavailability. Because cyclosporine or intensive therapy and BMT may be more frequently employed for treatment of refractory LCH or other hematological disorders in the future, specific surveillance of DDAVP kinetic in these patients must be performed.

Received January 13, 1997.

Revised February 19, 1997.

Accepted February 20, 1997.


    References
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 Introduction
 DDAVP kinetics
 Differential diagnosis and...
 References
 

  1. Maghnie M, Villa A, Aricò M, Larizza D, et al. 1992 Correlation between magnetic resonance imaging of posterior pituitary and neurohypophyseal function in children with diabetes insipidus. J Clin Endocrinol Metab. 74:795–800.[Abstract]
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