Cerebrospinal fluid (CSF) leaks may be caused from a variety of etiologies. Some of the most common sources include iatrogenic (otolaryngologic or neurologic surgery), traumatic (blunt or penetrating trauma), nontraumatic (bony erosion by tumor, infection, empty sella syndrome, meningoencephaloceles, congential defects), and spontaneous etiologies (dural sac weakness, meningeal diverticula, dural tear from spondylosis). An important component in the management of any CSF leak is proper identification and localization of the dural defect, which can originate from the anterior, middle, or posterior cranial fossas. The most common site of accidental or incidental surgical fractures is at the cribriform plate, where the bone is thick, the area immediately adjacent is thin, and the dura is very adherent.1
Fluorescein sodium is a fluorochrome dye commonly used to detect structures or details that are imperceptible to the human eye. A clinical application of fluorescein is its intrathecal administration to facilitate the diagnosis and localization of a CSF leak.2–5 Although this diagnostic technique is commonly used by otorhinolaryngologists and neurosurgeons, it is the anesthesia provider who most commonly administers the drug through an intrathecal drain or catheter. Intrathecal fluorescein may be associated with a variety of side effects and complications that have not been reported within the anesthesia literature. We present a case of status epilepticus in a patient who received intrathecal fluorescein to aid in the identification of a suspected CSF leak. The case report reviews potential complications associated with intrathecal fluorescein administration and emphasizes the need for anesthesia providers to be aware of these complications to appropriately manage them during the perioperative period.
A 59-year old woman was brought urgently to the operating room for progressive left periorbital pain and edema. Two days prior, the patient underwent extensive endoscopic sinus surgery and reconstruction for recurrent paranasal sinusitis. The patient was scheduled to undergo endoscopic ethmoid re-exploration for a suspected CSF leak. Her medical history was significant for well-controlled insulin-dependent diabetes mellitus and depression. Preoperatively, the surgical team requested that an intrathecal catheter be placed for the administration of fluorescein to aid in the detection of a CSF leak. The anesthesia team discussed the risks and benefits of an intrathecal catheter with the patient, including infection, bleeding, neurologic injury, arachnoiditis, and postdural puncture headache. The patient expressed an understanding of the risks and agreed to proceed with lumbar catheter placement.
After the placement of standardized monitors, the patient was placed in the left lateral decubitus position and sedated with IV fentanyl (50 μg) and midazolam (1 mg). A 20-G L3–4 intrathecal catheter was placed and free-flow of CSF confirmed. The patient was repositioned supine and anesthesia was induced with IV fentanyl (1.5 μg/kg), sodium thiopental (5 mg/kg), and succinylcholine (1.5 mg/kg) and maintained with isoflurane in a 1:1 air-oxygen mixture after tracheal intubation. No nondepolarizing muscle relaxants were used during the procedure.
Thirty minutes after induction, 50 mg of fluorescein (0.5 mL of 10% solution) diluted in 9.5 mL of CSF was administered through the intrathecal catheter at the surgeon's request. This is a standard dose and method of application described within the literature.2,5–7 Seventy minutes after administration, the patient developed seizure-like shaking of the lower extremities while still under anesthesia. Because the patient received her normal dose of insulin 2 H prior, it was initially believed that she may have been experiencing a hypoglycemic reaction. An arterial blood gas and electrolyte panel (including glucose) had been sent to the laboratory 5 minutes before the seizure-like episode, but the results were still pending. Therefore, the patient was treated with 12.5 g of a dextrose solution, midazolam 1 mg, and thiopental 125 mg. The symptoms resolved within 45 S. Another episode of lower extremity shaking was observed 20 minutes later. Repeat doses of thiopental (250 mg) and dextrose solution (12.5 g) were given and symptoms once again resolved within 45 S. Shortly after this episode, laboratory results became available. The arterial blood gas analysis and electrolytes were within normal limits (sodium 137 mM, potassium 3.8 mM, ionized calcium 4.8 mg/dL) and serum glucose was elevated (228 mg/dL). A third episode of generalized stiffness and shaking occurred at the end of the case, approximately 40 minutes later. Symptoms resolved spontaneously after 10 S. The patient was given a third dose of thiopental (250 mg) and transported to the intensive care unit (ICU) intubated and sedated due to concerns of possible continuing seizure-like activity. Of note, the patient was hemodynamically stable (heart rate and arterial blood pressure within 20% of baseline), well oxygenated (oxygen saturation 97%–100%), and normocapnic throughout the procedure. During the operative course, there was no clear surgical etiology (i.e., dural puncture, electrocautery stimulation, surgical bleeding, etc.) for the seizure-like activity.
On arrival to the ICU, the patient experienced intermittent episodes of decerebrate posturing and generalized tremors lasting up to 20 S. She was treated with an initial loading dose of fosphenytoin and a continuous midazolam infusion. Urgent neurology consultation concluded the patient was in status epilepticus. A bedside electroencephalogram showed nonspecific, generalized slowing but no potential epileptogenic alterations believed secondary to medication effect. A magnetic resonance image of the head demonstrated postoperative changes but no evidence of intracranial mass, hematoma, infarction, or meningitis. Analysis of CSF revealed pleocytosis and elevated protein, however, bacterial and fungal cultures were all negative.
Intermittent seizure activity persisted throughout the first postoperative day, as did frequent episodes of decerebrate posturing. She remained intubated and sedated until postoperative day 2, at which time the midazolam sedation and mechanical ventilation were weaned off. On postoperative day 3, the patient began demonstrating slight improvement in her cognitive status. The remainder of her hospital course was uneventful. She was transferred from the ICU to the hospital ward on postoperative day 3 and dismissed home on a stable dose of phenytoin 2 days later. The patient's cognitive status (short-term recall, calculations, word-finding) at hospital discharge remained slightly impaired. Her antiseizure medication was tapered and discontinued as an outpatient 6 Mo later. At that time, the patient's family reported her cognitive and functional status to be near baseline.
Kirchner and Proud were the first to describe the use of intrathecal fluorescein to identify and localize CSF rhinorrhea and otorrhea in 1960.2 Since that time, the technique has been used when other imaging modalities (computed tomography or magnetic resonance imaging) fail to locate the source of leak, or when intraoperative detection of CSF is necessary.2–5 Recently, intrathecal fluorescein has also been used to stratify the extent of skull base reconstruction required during endoscopic skull base surgery.8 Despite its relatively infrequent usage, it is still considered to be a clinically useful diagnostic tool.5,8,9
Although generally considered to be a benign intervention, the intrathecal administration of fluorescein has resulted in adverse events. Most cases report neurologic sequelae including lower extremity numbness, weakness, or spasticity, as well as drowsiness, nausea, confusion, and cranial nerve deficits.10–15 In some cases, these symptoms may progress to generalized tonic-clonic or absence seizures, including rare episodes of status epilepticus.11–14 Anecdotal examples of these complications have been reported within the neurologic and otorhinolaryngologic literature. However, there is a complete absence of these findings within the anesthesia literature, which is surprising due to the fact that anesthesia providers are the individuals most commonly administering this diagnostic compound.
The precise etiology and timing of seizure activity is often unclear. Most reports speculate that the drug or solution additives may cause direct central nervous system neuroactivation, meningeal irritation refractory to general anesthesia, or aseptic chemical meningitis. A canine model by Syms et al.16 demonstrated histopathologic changes of the central nervous system after intrathecal administration consistent with the introduction of an irritant material. Chemically mediated meningeal irritation seems plausible within our patient, as the CSF analysis was consistent with aseptic meningitis. Blood contamination of the neuraxis may have also contributed to seizure-like activity; however, the CSF analysis did not support this. In addition, no metabolic abnormalities were present, neuroimaging was unremarkable, there were no apparent surgical insults that may have resulted in seizure activity, and the osmolality of the injectate was similar to plasma and CSF (291 mOsm/L). Finally, while some suggest that contamination during intrathecal injection may be an underlying cause of a clinical presentation consistent with meningitis, the relatively short onset of symptoms described in this and many other cases makes an infectious etiology less likely.
The onset of symptoms after intrathecal administration may also be somewhat unpredictable. In a 1978 survey of the American Association of Neurological Surgeons, respondents who witnessed a neurologic complication after intrathecal fluorescein reported onset times ranging from 30 minutes to 12 H.10 The type and severity of symptoms did not seem to correlate with onset time or fluorescein dose. The symptoms in our patient responded to treatment with IV benzodiazepines and barbiturates, which is consistent with the successful treatment reported in other cases.11,13 Fortunately, most fluorescein-induced neurologic complications are reversible and typically resolve within 7–10 days.
Our case is unique in that the patient developed intermittent tonic-clonic activity while anesthetized with 1 MAC of isoflurane. Although clinical seizures have been reported during isoflurane anesthesia,17 isoflurane is generally not considered to produce electroencephalographic or clinical seizures in humans.18,19 In fact, it is recommended as treatment for status epilepticus in cases refractory to conventional IV medications.20–22 Limiting the use of nondepolarizing muscle relaxants during general anesthesia may be an important consideration for cases requiring intrathecal fluorescein. Although clinically apparent seizure activity during general anesthesia is quite rare, our case clearly demonstrates that the absence of diffuse muscle relaxation may aid in the early diagnosis and treatment of seizure activity.
In conclusion, intrathecal fluorescein sodium may be a valuable diagnostic tool in the identification and localization of CSF leaks. Anesthesia providers are commonly asked to administer the drug via an intrathecal catheter or spinal drain and should be aware of potential complications that may arise. Because intrathecal fluorescein administration is considered an “off-label” use of the drug, preoperative informed consent should include a detailed discussion of neurologic sequelae that may be associated with the drug. In addition, baseline neurologic status, including preexisting cognitive and sensorimotor deficits, should be clearly established and documented within the medical record. Limited evidence suggests that fluorescein injection in patients with a history of seizures, hydrocephalus, spinal stenosis, acute brain injury, cerebral edema, or other neurologic conditions be avoided.23 Once intrathecal fluorescein is administered, patients should be monitored for a minimum of 12 H with frequent neurologic examinations and seizure precautions. If neurologic complications develop, all possible etiologies should be thoroughly explored and excluded before attributing the complication to fluorescein administration. Seizure activity resulting from intrathecal fluorescein can be successfully treated with IV benzodiazepines or barbiturates.
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