Spontaneous Intracranial Hypotension-HypovolemiaAssociated With Tacrolimushead_1701 1386..••

Andrew H. Ahn, MD, PhD; Brian D. Berman, MD; William P. Dillon, MD

There is little precedent for a medication-induced spontaneous intracranial hypotension/cerebrospinal fluid (CSF) hypo-volemia (SIH). This case history of a woman with low CSF pressure, orthostatic headache, and radiographic findings consistentwith SIH but without a detectable leak was notable for its association, both onset and resolution, with the use of the calcineurininhibitor tacrolimus (FK506). A literature review for potential causes of a tacrolimus-induced CSF hypotension suggests manypotential mechanisms of action, including effects on blood brain barrier and dural compliance, and supports further vigilancefor this condition in the medically complex setting of tacrolimus use.

Key words: headache, low pressure syndrome, tacrolimus

Spontaneous intracranial hypotension-hypovolemia(SIH) is a disorder of intracranial cerebrospinal fluid(CSF) hypovolemia.1-3 The common clinical presen-tation of SIH is orthostatic headache, including theprompt onset of dull head pain upon arising fromsitting or lying down, usually with prompt resolutionof pain upon recumbency. Clinical investigation ofSIH is notable for a low opening pressure on lumbarpuncture, and is usually accompanied by a constel-lation of magnetic resonance imaging (MRI) find-ings, including diffuse dural enhancement, duralvenous dilatation, and a sagging appearance of theposterior fossa structures with flattening of the pons.The clinical spectrum of SIH is variable, and can belife-threatening.4 A high-volume lumbar autologousepidural blood patch is often curative, even withouta clear localization of the leak, but a more localizedapproach is thought to increase the likelihood ofsuccessful treatment. Computerized tomography(CT) myelography, and more recently MRI myelog-raphy, can localize the presumptive CSF leak, whichis most commonly found at the mid-thoracic spine,

in association with an arachnoid cyst, an incompe-tent nerve root sleeve, a ventral transdural osteo-phyte, or herniated disc.5 Occasionally an opensurgical procedure is necessary to close the duraldefect. However, in a significant number of patients,despite detailed imaging studies and clinical featuresof SIH, no apparent CSF leak is detected. Wepresent such a case of SIH/CSF hypovolemia,notable for its marked association with tacrolimus.

CASE REPORTThis 50-year-old woman, notably without a prior

headache history, underwent orthotopic cadavericliver transplant, and concurrently started tacrolimusimmunosuppression. Within 2 weeks of the trans-plant, in the setting of normalizing markers of liverfunction, the patient had the new onset of a dullorthostatic headache. Notably, and with a similaronset, the patient had the new onset of episodicheadache attacks, characterized by throbbingholocephalic head pain accompanied by nausea, vom-iting, photophobia, phonophobia, and exacerbation ofpain with exertion. Despite the resolution of theorthostatic headache within 8 months, these acuteepisodic attacks remained severe and frequent, 3 ormore times per week, with a consistent response torizatriptan.

The referring neurologist noted the hallmarksof SIH on MRI of the brain, but radionuclide

From the Department of Neurology, University of CaliforniaSan Francisco, San Francisco, CA, USA (A.H. Ahn and B.D.Berman); Department of Radiology, Neuroradiology Section,University of California San Francisco, San Francisco, CA,USA (W.P. Dillon).

Address all correspondence to A.H. Ahn, University of FloridaDepartment of Neurology, 100 South Newell Dr., Box 100236,McKnight Brain Institute L3-100, Gainesville, FL 32610, USA.

Accepted for publication March 29, 2010.Conflict of Interest: The authors report no conflicts of interest.Patient has provided written consent.

1386 September 2010

cisternography did not provide evidence for a leak.Two presumptive autologous lumbar epidural bloodpatches produced marked but only temporary reduc-tion of the frequent migrainous headaches. RepeatMRI of the brain at our institution revealed the per-sistence of diffuse dural enhancement, dural venousdilatation, and a flattened pons (Figure A). MRI ofthe entire spine did not localize a dural lesion sugges-tive of a CSF leak. Upon CT myelogram of the spinean opening pressure of 0 mm of water was obtained,

verifying an abnormally low pressure, but failed todetect extradural extravasation of contrast, even afterdelayed imaging. On successive studies, 3 repeatedhigh-volume autologous epidural blood patches atthe lumbar, thoracic, and cervical levels providedextended but only temporary headache-free periodsof 4-8 weeks.

We hypothesized that the myelogram failed tolocalize the leak because there was insufficient pres-sure within the dural sac to move contrast, and

A

C

B

Figure.—(A) Sagittal T1WI without contrast demonstrates effacement of the pre pontine cistern, downward displacement of thefloor of the third ventricle, mamillary bodies, and cerebellar tonsils, as well as horizontal orientation of the infundibular stalk of thepituitary gland. Note compression of the basilar artery by the pons. Prominence of the dural venous sinuses is also present. Inset:coronal T1 with gadolidium demonstrates diffuse dural enhancement and subdural effusions. These findings are consistent withintracranial CSF hypovolemia (SIH). (B) Sagittal T1WI MR without contrast, 22 months following initial scans, and 6 monthsfollowing withdrawal of tacrolimus, demonstrates a normalization of the downward displacement seen in multiple prior studies.Inset: coronal T1 with gadolidium demonstrates marked resolution of the dural enhancement and subdural effusion. (C) Pressurevolume curve during the infusion of Elliot’s B artificial CSF prior to CT myelogram and radionuclide cisternography. A slowovernight infusion at 15 cc per hour for 10 hours did not markedly change CSF pressure, but bolus infusion of 10 cc and 30 cc ofCSF demonstrated a pressure-volume relationship consistent with a functional hypovolemia. CSF = cerebrospinal fluid;CT = computerized tomography; SIH = spontaneous intracranial hypotension-hypovolemia.

Headache 1387

infused Elliot’s B artificial CSF through an intrathe-cal catheter, immediately prior to concurrent radio-nuclide cisternography, CT and MRI myelography.Bolus infusions of artificial CSF restored normalpressure only after a total volume of 40 cc, andwhose pressure-volume curve was suggestive of afunctional hypovolemia (Figure C). However,neither cisternography nor myelography localizedthe leak, and a large volume epidural blood patchagain only temporarily reduced the headache fre-quency, and did not result in any interval changes onrepeated MRI of the brain.

The patient was medically managed with caffeineand vitamin A for an additional 10 months without achange in her episodic headaches, until the patient’simmunosuppression was switched from tacrolimus tomycophenylate mofetil. The patient’s headacheattacks promptly became less frequent, and resolvedcompletely within 2 months. At 6 months after thewithdrawal of tacrolimus, MRI of the brain showedsubstantial normalization of the meningeal enhance-ment and other structural changes noted above(Figure B). There have been no further headaches inthe subsequent 3 years.

DISCUSSIONAlthough orthostatic headache is not always

present in SIH,2 it was an early and prominentfeature of this patient’s headache. When present, theorthostatic aspect of the headache often graduallydeclines despite the persistence of the underlyinghypotension-hypovolemia. Here, the persistence ofabnormally low CSF opening pressures and charac-teristic hallmarks of SIH on MRI of the brain wereclearly documented, even after the resolution of theorthostatic sign.The enduring feature of this woman’sheadache and associated SIH were frequent episodicattacks consistent with the diagnosis of migrainewithout aura, which is also common in this condition.2

In addition, remissions from the migrainous attacksfollowing epidural blood patch is highly consistentwith the relationship of these attacks to the SIH. Theinfusion of artificial CSF prior to diagnostic myelo-gram revealed a pressure-volume curve (Figure C)that confirmed a functional under-filling of this CSF-filled space.

Headache is a common side effect of tacrolimusimmunosuppression,6 and its evaluation is particu-larly challenging because it occurs amidst a host ofpotential causes for neurological complications aftertransplantation,7 and tacrolimus-related encephal-opathy and long-term cognitive changes are well-documented.8 Moreover, in the perioperative settingof compromised hepatic function, the presence ofintracranial hypertension is the more commonfinding, and would obscure the existence of a moresubtle opposing effect by tacrolimus.

If present, there are several potential mecha-nisms underlying a tacrolimus-induced CSF hypo-volemia. Tacrolimus interacts with a large family ofconserved proteins called immunophilins, which areimplicated in a broad range of biochemical processes,including protein folding, receptor signaling, proteintrafficking, and transcription.9 Tacrolimus forms acomplex with the major immunophilin, FK506-binding protein, and inhibits calcineurin, a key signal-ing enzyme in T-lymphocyte activation.10

Because the immunophilins and calcineurin areboth present at high levels in discrete regions of thebrain,11 it is presumed that the CNS effects of tacroli-mus act through one of the many potential actions ofthese proteins.There are many potential mechanisms,including an increase in cerebrovascular tone,12 achange in blood brain barrier function,13 or a suppres-sion of nitric oxide production.6,14 Direct modes ofaction of tacrolimus could include the inhibition ofCSF production, the facilitation of its absorption, or achange of vascular tone that could cause a subtledisruption of the CSF compliance of the thecal sacaround the spinal cord.

CONCLUSIONSThis single-case association of SIH with tacroli-

mus is purely hypothetical, as many cases if SIH ariseand resolve spontaneously without a detecable leak.However, the onset and resolution of the headacheand MRI findings coincide remarkably with the startand discontinuation of tacrolimus. Although ourcurrent understanding of the mechanism of tacroli-mus action does not explain its association with SIH/CSF hypovolemia, we suggest it is important toconsider the potential role of tacrolimus and other

1388 September 2010

medications when evaluating a patient with thiscondition.

Acknowledgment: The authors gratefully acknowl-

edge fruitful discussion with Dr. B. Mokri regarding this

case.

STATEMENT OF AUTHORSHIP

Category 1(a) Conception and Design

Andrew H. Ahn, William P. Dillon(b) Acquisition of Data

Andrew H. Ahn, Brian D. Berman, William P.Dillon

(c) Analysis and Interpretation of DataAndrew H. Ahn, William P. Dillon

Category 2(a) Drafting the Article

Andrew H. Ahn(b) Revising It for Intellectual Content

Andrew H. Ahn, Brian D. Berman, William P.Dillon

Category 3(a) Final Approval of the Completed Article

Andrew H. Ahn, Brian D. Berman, William P.Dillon

REFERENCES

1. Fishman RA, Dillon WP. Dural enhancement andcerebral displacement secondary to intracranialhypotension. Neurology. 1993;43:609-611.

2. Mokri B. Spontaneous cerebrospinal fluid leaks:From intracranial hypotension to cerebrospinal fluidhypovolemia – evolution of a concept. Mayo ClinProc. 1999;74:1113-1123.

3. Schievink WI. Spontaneous spinal cerebrospinalfluid leaks and intracranial hypotension. JAMA.2006;295:2286-2296.

4. Evan RW, Mokri B. Spontaneous intracranialhypotension resulting in coma. Headache. 2002;42:159-160.

5. Dillon WP. Spinal manifestations of intracranialhypotension. AJNR Am J Neuroradiol. 2001;22:1233-1234.

6. Ferrari U, Empl M, Kim KS, Sostak P, ForderreutherS, Straube A. Calcineurin inhibitor-induced head-ache: Clinical characteristics and possible mecha-nisms. Headache. 2005;45:211-214.

7. Saner F, Gu Y, Minouchehr S, et al. Neurologicalcomplications after cadaveric and living donor livertransplantation. J Neurol. 2006;253:612-617.

8. Chegounchi M, Hanna MG, Neild GH. Progressiveneurological disease induced by tacrolimus in a renaltransplant recipient: Case presentation. BMCNephrol. 2006;7:7.

9. Kang CB, Hong Y, Dhe-Paganon S, Yoon HS. FKBPfamily proteins: Immunophilins with versatile bio-logical functions. Neurosignals. 2008;16:318-325.

10.Clipstone NA, Crabtree GR. Identification of cal-cineurin as a key signalling enzyme in T-lymphocyteactivation. Nature. 1992;357:695-697.

11.Dawson TM, Steiner JP, Lyons WE, Fotuhi M, BlueM, Snyder SH. The immunophilins, FK506 bindingprotein and cyclophilin, are discretely localized in thebrain: Relationship to calcineurin. Neuroscience.1994;62:569-580.

12.Dethloff T, Hansen BA, Larsen FS. Tacrolimus ame-liorates cerebral vasodilatation and intracranialhypertension in the rat with portacaval anastomosisand hyperammonemia. Liver Transpl. 2004;10:922-927.

13.Kochi S, Takanaga H, Matsuo H, Naito M, Tsuruo T,Sawada Y. Effect of cyclosporin A or tacrolimus onthe function of blood-brain barrier cells. Eur J Phar-macol. 1999;372:287-295.

14.Sasaki T, Hamada J, Shibata M, Gotoh J, Araki N,Fukuuchi Y. FK506 abrogates delayed neuronaldeath via suppression of nitric oxide production inrats. Brain Res. 2004;1009:34-39.

Headache 1389