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
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Introduction
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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 146122 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 3036 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. 1
). 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).
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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. 1
).
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DDAVP kinetics
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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.
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Differential diagnosis and literature review
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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.
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