
==== Front
Interv Pain Med
Interv Pain Med
Interventional Pain Medicine
2772-5944
Elsevier

S2772-5944(22)00096-6
10.1016/j.inpm.2022.100105
100105
Letters to the Editor
Encephalopathy after unintentional intrathecal gadolinium: A letter to the editor
Moradian Maxim a
Tekmyster Gene gene.tekmyster@gmail.com
d∗
Wei Jason J. Jason.Wei.DO@gmail.com
c
Avetisian Henry a
Acharya Jayant N. b
Furman Michael B. e
a Interventional Spine and Orthopedic Regenerative Experts, PC (iSCORE). California Sports and Spine Institute, PC (CSSI), 51 N. 5th Ave, Suite 301, Arcadia, CA, 91006, USA
b Department of Neurology, EC037. Penn State Hershey Medical Center, 30 Hope Drive, Hershey, PA, 17033, USA
c UCLA Spine Center, 1131 Wilshire Blvd, Suite 100, Santa Monica, CA, 90401, USA
d Assistant Professor of Clinical Orthopaedic Surgery, Keck Medicine of USC, Toyota Sports Performance Center, 555 N. Nash Street, El Segundo, CA, USA
e OSS Health, 1855 Powder Mill Road, York, PA, 17402, USA
∗ Corresponding author. gene.tekmyster@gmail.com
17 6 2022
9 2022
17 6 2022
1 3 10010516 1 2022
23 5 2022
23 5 2022
© 2022 The Authors
2022
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Objective

Raise awareness of gadolinium encephalopathy, a rare cause of neurological symptoms.

Setting

An L5-S1 interlaminar epidural steroid injection (IL-ESI) was performed with a gadolinium-based contrast agent (GBCA) due to the patient's history of allergic reaction to iodine-based contrast agents.

Discussion

Several hours after administration of GBCA, the patient had nausea and vomiting with altered mental status. Patient was treated with dexamethasone IV, and was discharged on day 2. Patient had no residual deficits at follow-up two weeks later. Current literature shows that caution should be used to prevent inadvertent intrathecal GBCA, and doses >2.0 mmols are associated with serious adverse effects, including death.

Conclusions

Intrathecal administration of GBCAs should be limited to less than 0.5 mmol. If adverse effects are experienced, IV steroids should be administered as soon as possible, and a CSF drain should be considered.
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pmcDear Editor,

Contrast media is utilized for performing safe and effective fluoroscopically guided injections. Prior to delivery of the injectate to the intended target, real-time observation of contrast flow utilizing continuous fluoroscopy or digital subtraction imaging is used to confirm non-vascular epidural spread and confirm appropriate site of medication delivery.

Common agents utilized during procedures include non-ionic iodinated contrast medium, ie iohexol. In patients with prior documented hypersensitivity reaction to iodinated contrast medium, premedication protocols, no contrast agent administration, or contrast media alternatives such as Gadolinium are considered.

Gadolinium-based contrast agents (GBCAs) are FDA approved for Magnetic Resonance Imaging (MRI) studies requiring intravenous (IV) contrast media to enhance image quality. Eight of these agents are currently approved by the FDA. In addition to its use as an MRI contrast agent, GBCAs may be used during interventional spine procedures as an alternative for patients who report iodine-based contrast agent hypersensitivity reactions.

In 2021, Benzon et al. recently published a multi-society Practice Advisory (PA) on the use of contrast agents in interventional pain procedures with a large focus on GBCAs and recommendations on their use [1]. This manuscript's authors defer to the PA for their recommendations.

Previous case reports on encephalopathy after unintentional intrathecal gadolinium injection were published before the PA by Benzon et al. [1] Since we are reporting our 2012 complication after the 2021 PA, this letter's conclusions take into consideration these PA recommendations as they relate to our patient and these previous case reports.

We present a case of a patient with an unusual cause of encephalopathy post inadvertent intrathecal gadolinium administration, a rare cause of altered mental status (AMS) that should quickly be recognized. Awareness should help avoid the clinical syndrome or improve outcomes if expedient treatment is offered, including IV steroid. The use of GBCA for interventional spine procedures is off-label, as it is only approved for IV use [1].

Our 2012 case involves a 67-year-old female with a past medical history of depression, hypothyroidism, hyperlipidemia, hypertension, osteoarthritis, and restless leg syndrome who was being managed at our interventional spine center for complaints of right upper buttock pain radiating down the right lower limb. Her lumbar spine MRI demonstrated moderate foraminal stenosis due to anterolisthesis at L4 on L5, moderate disc desiccation at L5-S1, and bilateral facet arthropathy. Based on the patient's persistent and worsening radicular symptoms and imaging findings, the patient underwent an L5-S1 interlaminar epidural steroid injection (IL-ESI) with a right paramedian approach using GBCA (gadodiamide) due to the patient's self-reported history of reaction (bronchospasms) to iodinated contrast media (ICM). Of significant importance, the 2021 PA recommendations by Benzon et al. were not yet published.

The right L5-S1 epidural space was localized with loss of resistance technique using an 18 Gauge, 5-inch Touhy needle. Approximately 2 ml (1 mmol) of gadodiamide was injected for contrast media flow confirmation and intrathecal spread of the gadolinium contrast agent was suspected. The needle was withdrawn without anesthetic or steroid administration. The needle was re-inserted on the contralateral side with the goal of treating the L5-S1 pathology with an L5-S1interlaminar approach from the contralateral side since it was felt to be the best treatment option.

After final needle tip confirmation in the epidural space with additional gadolinium, optimal epidural spread was noted and a mixture of triamcinolone, preservative-free lidocaine 1%, and saline was injected. The total gadolinium volume injected was 4 ml [2 mmol total, 2 mL (1 mmol) each on the right and left sides]. The initial 2 ml (1 mmol) was suspected to be intrathecal. The patient was educated on the possible development of post-dural headache and recommended hydration and caffeine as a treatment/prophylaxis. After spending at least 30 min under observation in recovery, she was discharged in stable condition.

Within about 2 h after the procedure, the patient called to report unusual vomiting. The patient declined antiemetic medication (ondansetron) at that time. Approximately 4 h after the procedure, the patient's husband communicated with the on-call physician, notifying him of a second vomiting episode with altered mental status (AMS). The patient was advised to go immediately to the community emergency department (ED) for further evaluation and treatment.

She presented to the local ED, where the physician noted tachycardia (118 BPM), hypertension (184/81), hypoxia (O2 Sat 84%), and poor attention, requiring frequent redirecting without focal neurological deficits. Laboratory testing did not reveal any significant hematologic, electrolyte, or metabolic abnormalities. The patient was given normal saline, ondansetron, and lorazepam. Her head CT scan without contrast (Fig. 1) demonstrated diffuse cerebral edema with effacement of sulci (Fig. 1). The patient was subsequently transferred to a tertiary hospital system, with the diagnosis of encephalopathy, AMS, and hypoxia.Fig. 1 CT of the brain on admission to the acute care hospital demonstrating diffuse cerebral edema and effacement of sulci (arrows).

Fig. 1

As shown in Fig. 2, the patient's non-contrast brain MRI T1-weighted and fluid attenuated inversion recovery (FLAIR) sequences showed bright (hyperintense) signals in the sulci and ventricles instead of the normal dark (hypointense) signals. These findings were consistent with the presence of Gadolinium in the CSF spaces. EEG demonstrated lack of occipital dominant rhythm with diffuse slowing without epileptiform activity or electrographic seizures. These findings were consistent with encephalopathy.Fig. 2 MRI imaging of the brain on admission to the acute care hospital. No additional contrast was administered at time of imaging, the enhancement noted on these images was due to the gadolinium (inadvertent intrathecal) administration during the pain procedure. (CSF should be hypointense on T1 and FLAIR images, not hyperintense as seen here. Compare to absence of enhancement seen in Fig. 3.)

Fig. 2

Due to the temporal association between the patient's symptoms and intrathecal injection of gadolinium, neuro-imaging findings confirming the presence of gadolinium within the CSF spaces, and the lack of any other laboratory abnormalities and alternative conditions, the neurology team diagnosed the patient with intrathecal gadolinium encephalopathy. The patient had already received a dose of dexamethasone (6 mg) by IV route in the ER. Upon transfer out of the ED, dexamethasone 4 mg IV every 6 h was administered for a total of 4 doses. Her mental status improved rapidly and a follow up examination the next day demonstrated normal orientation, attention, and memory. The patient was subsequently discharged.

She received a neurology follow-up at one and six months after discharge. She continued to do well without persistent sequelae. A repeat brain MRI 5 months post injection showed resolution of the hyperintense signals in the CSF spaces in T1 and FLAIR images (Fig. 3).Fig. 3 MRI imaging of the brain 5 months post-injection showing resolution of gadolinium enhancement (Compare to the enhancement seen in Fig. 2.).

Fig. 3

Upon follow up evaluation by phone two weeks after the procedure, the patient reported improvement in back and radicular pain overall and return to baseline with no remaining headaches, cognitive issues, or nausea since discharge.

Precise needle placement and targeted medication delivery is paramount during interventional spine procedures. Contrast enhanced, fluoroscopic guided spine procedures provide optimal safety and efficiency in delivering stated medication to the targeted structures. Suboptimal needle tip position and injection can result in dural punctures, intrathecal injection, spinal anesthesia, vascular injections, and/or incomplete target structure coverage. Dural punctures can lead to complications including CSF leaks, headaches, cranial nerve palsies, subdural hematomas, cerebral venous thrombosis, meningitis, and death [2,3].

Intravascular injections can cause serious adverse effects (AEs), including respiratory compromise, seizures, cord infarction, stroke, and/or even instantaneous death [2,[4], [5], [6], [7]]. Factors associated with increased intravascular injection risk are the transforaminal epidural (compared to interlaminar) approach, cervical/thoracic/upper lumbar (compared to lower lumbar/sacral) level approach, and adhesiolysis procedures, to name a few [[8], [9], [10], [11]]. Aspiration as a tool to detect a vascular injection is insufficient on its own to provide complete safety [4,[7], [8], [9]]. In 2015 the FDA endorsed a safe-use consensus paper with strong recommendations to inject contrast agents under live fluoroscopy and/or digital subtraction imaging to verify non-vascular placement [12,13].

The standard loss of resistance technique is inherently unreliable on its own to verify access to the epidural space [14,15]. Evidence based literature shows loss-of-air-resistance without fluoroscopic guidance and contrast enhancement is inaccurate in 25–30% of injections, and loss-of-saline-resistance inaccurate 8% of the time [14,15].

Although gadolinium is generally considered to be a safe contrast agent, encephalopathy has been associated previously with both IV and intrathecal injection. Gadolinium encephalopathy is a relatively new concept first coined by Maramattom et al., in 2005 and is associated with poor renal function with subsequent accumulation of IV-administered gadolinium [1,[17], [18], [19], [20], [21]]. Even with normal renal function, IV-administered gadolinium is known to deposit into tissues, including the brain [1,[19], [20], [21], [22]].

Intrathecal injection of gadolinium is considered off-label use for all forms of GBCAs. Intrathecal GBCA use has been adopted by neurologists and neurosurgeons due to better sensitivity for subtle CSF leaks after CT cisternography fails to find the source of the leak [23,24]. These imaging studies, however, are not without AEs. Patel et al. performed a systematic review including 1036 patients which showed a 13% rate of AEs (130 patients), most commonly postural headache (108 patients) [24]. Their review also examined 10 case reports of serious AEs from administration of intrathecal gadolinium, which included 1 death. Our literature review found 5 additional case reports of serious AEs from intrathecal gadolinium [[25], [26], [27], [28], [29], [30]]. The manuscript by Nayak et al. had an additional case report (for a total of 2 case reports) which was not reported in the review by Patel et al. [25]. Of these 15 total case reports of serious AEs, 4 were due to ESIs with accidental intrathecal injection [27,28,31,32].

Current literature review demonstrates adverse effects with intrathecal gadolinium dose equal to or greater than 0.5 mmol or 0.73 μmol/g brain (assuming 1400g adult brain) [23,24,[26], [27], [28], [29], [30],35]. Shah et al. presented a case of a pain pump catheter evaluation with 0.5 mmol of gadodiamide which resulted in generalized seizures and 45 days of hospitalization [30]. This is the lowest dose of intrathecal gadolinium that caused serious adverse effects found in the current literature. Halvorsen et al. performed a prospective safety study with 149 pts comparing a 0.25 mmol vs 0.5 mmol dose of intrathecal gadobutrol and concluded that both doses were safe, with non-serious AEs occurring in 76% of patients, most commonly nausea, headache, and dizziness, the majority of which resolved within 24 h [23]. Tali et al. performed a prospective safety study with 95 patients who received up to 0.5 mmol of intrathecal gadopentetate dimeglumine and also showed that patients only experienced non-serious AEs of headaches (20%), nausea (6%), and vomiting (2%) that lasted less than 24 h [35]. In the review by Patel et al., all of the patients with non-serious AEs received 1 mmol or less of GBCA, mostly gadopentetate dimeglumine [24]. Additional studies by Dogan et al. and Algin et al. add an approximate additional 266 patients who safely received 0.25 mmol of intrathecal GBCA which is consistent with the aforementioned studies [36,37]. Benzon et al. reported with low certainty the occurrence of encephalopathy after intrathecal doses as low as 1.5 mL of gadobutrol (1.5 mmol), based off of Popescu et al.’s case report [1,28]. Shah et al.’s case report may represent a case with a lower dose of 0.5 mmol (gadodiamide) that caused encephalopathy (see Table 1).

If serious AEs occur, one must have high suspicion for gadolinium encephalopathy as the neurological symptoms may present similarly to an intracranial pathology and subsequent imaging may lead to a false-positive for intracranial hemorrhage [25,27]. Symptoms may include cognitive decline, headache, nausea, vomiting, dizziness, tremors, hallucinations, seizure, dysarthria, hearing deficit, vision deficit, taste alteration, hypertension, respiratory distress/failure, tachycardia, fever, chills, pruritus, back pain, paresthesias, and fatigue [23,24,34]. In the event that gadolinium encephalopathy is suspected, Li et al. suggests that draining CSF is a life-saving procedure, and that glucocorticoids may also help [38]. Of the 15 serious AE case reports, glucocorticoids were given to 7 patients, and CSF drains were used in 3 and considered in 1 (see Table 2) [25,31,[38], [39], [40]]. In this case report, a CSF drain was not placed, but the patient was given glucocorticoids within hours. Prompt administration of glucocorticoids are used to reduce possible cerebral edema that is seen on imaging [38,39,41]. Benzon et al. did not specify what measures to take but did recommend institution of immediate supportive measures [1].Table 1 Gadolinium-based Radiocontrast agents and their molar concentrations [33,39].

Table 1Trade Name	Generic Name	Structure	Molar Concentration (mmol/L)	
Ablavar, Vasovist	Gadofosveset trisodium	Linear ionic	0.25	
Artirem, Dotarem, Clariscan	Gadoterate meglumine	Macrocyclic ionic	0.5	
Eovist, Primovist	Gadoxetate disodium	Linear ionic	0.25	
Gadavist, Gadovist	Gadobutrol	Macrocyclic nonionic	1.0	
Magnevist	Gadopentetate dimeglumine	Linear ionic	0.5	
MultiHance	Gadobenate dimeglumine	Linear ionic	0.5	
Omniscan	Gadodiamide	Linear nonionic	0.5	
Optimark	Gadoversetamide	Linear nonionic	0.5	
ProHance	Gadoteridol	Macrocyclic nonionic	0.5	

Table 2 Cases reports of gadolinium neurotoxicity.

Table 2Study	Intrathecal Dose in mmol (mL), Type of GBCA	Treatments Administered	
CSF drain	Glucocorticoids	Other	
This case report. Moradian et al.	1 mmol (2 mL),
Gadodiamide		dexamethasone 6 mg IV x1, 4 mg IV x4	ondansetron, lorazepam	
Arlt et al., 2007 [39]	10 mmol (20 mL),
Gadopentetate dimeglumine		dexamethasone 40 mg IV x1	antipsychotics for aggression and hallucinations	
Besteher et al., 2019 [40]	2 mmol (2 mL),
Gadobutrol		prednisolone 100 mg x1	dimentindene 4 mg, ranitidine 50 mg, intubation	
Kapoor et al., 2010 [31]	4 mmol (8 mL),
Gadodiamide		methylprednisolone IV	keppra, mag sulfate, intubation	
Li et al., 2008 [38]	7.5 mmol (15 mL),
Gadopentetate dimeglumine	Lumbar cisterna @ 0.3–0.5 mL/min	methylprednisolone 1g IV QD x7d	chlorpromazine 50 mg ​+ ​phenergan 50 mg IV x2d, then naloxone 4 mg x7d	
Malalur et al., 2020 [26]	6 mmol (12 mL),
Gadopentetate dimeglumine		high-dose IV dexamethasone	supportive care	
Nayak et al., 2013 [25]	5 mmol (10 mL),
Gadopentetate dimeglumine	ventriculostomy set to 0 mmHg, lumbar drain placed 2d after gad admin		anti-epileptics for status epilepticus, ET tube converted to trach	
Park et al., 2010 [42]	3 mmol (6 mL),
Gadopentetate dimeglumine			IVF, anti-epileptics, supportive care	
Platt et al., 2020 [27]	2 mmol (2 mL),
Gadobutrol			levetiracetam	
Popescu et al., 2018 [28]	1.5 mmol (1.5 mL),
Gadobutrol			intubation	
Provenzano et al., 2019 [34]	2.5 mmol (5 mL),
Gadoteridol	neurosurgery considered CSF drain			
Reeves et al., 2017 [43]	2 mmol (2 mL),
Gadobutrol			midazolam for spasms	
Samardzic et al., 2015 [32]	2 mmol (4 mL),
Gadodiamide		dexamethasone 4 mg IV q6hr ×4 doses		
Shah et al., 2015 [30]	0.5 mmol (1 mL),
Gadodiamide			intubated	
Singh et al., 2016 [41]	5 mmol (10 mL),
Gadopentetate dimeglumine	EVD left open to drain, lumbar drain placed after edema improved on day 2	dexamethasone IV	intubation, hyperventillation, hypertonic saline, anti-epileptics	

A practical and safe alternative in a patient with hypersensitivity reactions to ICM, is not using any type of contrast media at all for the procedure. Since gadolinium is poorly visualized under fluoroscopic guidance (even when digital subtraction imaging is utilized), especially with lower molar concentration GBCAs, it is tempting to use even higher volumes [44]. Since intrathecal gadolinium is significantly more dangerous than an intrathecal injection of steroid, some interventionalists choose not to use any contrast agent at all. An obvious drawback is possible inaccurate needle placement which may occur 25%–30% of the time when relying solely on loss of resistance techniques with fluoroscopic imaging but without contrast confirmation [15]. In addition, intravascular injection may occur if relying on blood flashback in the needle hub or with aspiration, which is highly specific (97%–97.9%), but not very sensitive (44.7%–45.9%) [8,9].

The use of gadolinium may also be considered with injections with lower risk of intrathecal administration such as peripheral skeletal joints, facet joints, sacroiliac joints, or other procedures such as medial/lateral branch blocks, and even advanced procedures such as provocation discography [1,45].

This case report presents a patient who sustained a serious AE from the intrathecal administration of 2 mmol of Omniscan (Gadodiamide) during an interventional pain procedure and also reviews other patients with similar AEs in the currently available literature. Gadolinium-based contrast agents are commercially available in a wide variety of concentrations ranging from 0.25 to 1 mmol/mL. Due to the variation in GBCAs, the dose of gadolinium should be reported in volume, type and concentration of GBCA used [1]. The agent used should be properly named due to differences in the chelators for the gadolinium ion and possible relationship to immunogenicity [1]. If the patient suffers from a serious AE to intrathecal gadolinium, IV glucocorticoids are indicated on an urgent/emergent basis, with appropriate treatment guided by facility policy and available best practices, which fall outside the scope of this publication. In Table 3, we provide a premedication regimen list as a reference. For iodinated contrast media hypersensitivity reactions, multiple strategies exist, including premedication (steroids/antihistamine), allergy testing and/or both, and doing the procedure without contrast media. GBCA may have a reasonable role in peripheral procedures where there is no intrathecal delivery risk. However, GBCA should not be used for neuraxial spine procedures where there is a risk of unintended subarachnoid or intrathecal injection. Ultimately, the clinician must weigh the risks of contrast agent usage vs the risks of using none at all for each patient, contrast agent, and adjunct medications.Table 3 Premedication regimens for contrast media reactions.

Table 3American College of Radiology [47]	
General Option 1	Prednisone-based: 50 mg prednisone PO at 13 h, 7hr, and 1hr before contrast medium administration, + 50 mg diphenhydramine IV, IM, or PO 1hr before contrast administration	
General Option 2	Methylprednisolone-based: 32 mg methylprednisolone by mouth 12hr and 2hr before contrast administration. +/− diphenhydramine 50 mg	
Emergency Option 1	methylprednisolone 40 ​mg IV or hydrocortisone 200 ​mg IV q4hr until contrast administration ​+ ​diphenhydramine 50 ​mg IV 1hr before	
Emergency Option 2	dexamethasone 7.5 mg IV q4hr until contrast administration ​+ ​diphenhydramine 50 ​mg IV 1hr before	
Emergency Option 3	methylprednisolone 40 ​mg IV or hydrocortisone 200 ​mg IV ​+ ​diphenhydramine 50 ​mg IV 1hr before (No evidence of efficacy, use only when no alternatives)	
Benzon et al [1]	
Emergency Option 1	methylprednisolone 40 ​mg IV or hydrocortisone 200 ​mg IV q4hr until contrast administration ​+ ​diphenhydramine 50 ​mg IV 1hr before	
Emergency Option 2	dexamethasone 7.5 mg IV q4hr until contrast administration ​+ ​diphenhydramine 50 ​mg IV 1hr before	
Kwon et al [46]	
Mild	chlorpheniramine 4 mg IV 1hr prior	
Moderate	methylprednisolone 40 ​mg ​+ ​chlorpheniramine 4 mg IV 1 h prior	
Severe	prednisolone 50 mg PO 13 h, 7hr, and 1hr prior	
Wu et al [48]	
Lasser et al.	methylprednisolone 32 mg PO 6hr and 2hr before contrast administration	
ACR	as above	
ESUR	prednisolone 30 mg PO or methylprednisolone 32 mg PO 12hr and 2hr before contrast administration	
Schopp et al [49]	
Elective	ACR as above	
Emergency Option 1	methylprednisolone 40 mg IV q4hr, or hydrocortisone 200 mg IV q 4 h until contrast administration ​+ ​diphenhydramine 50 mg IV 1hr before	
Emergency Option 2	dexamethasone 7.5 mg IV q4hr, or betamethasone 6 mg IV q4hr until contrast administration ​+ ​diphenhydramine 50 mg IV 1hr before	
Emergency Option 3	Omit steroids entirely (no desirable) ​+ ​diphenhydramine 50 ​mg IV (antihistamines alone have not been proven to reduce occurrence of reactions)	

Future Research/Topics: We challenge scientists and interventionalists to search for safer agents that can be used to identify inadvertent intrathecal injection, eg. iron oxides of manganese [33]. The majority of intrathecal GBCA cases used gadopentetate dimeglumine or gadobutrol. We question if there is a GBCA that is safer than others for intrathecal use. In a case where the interventionist decides to proceed with the use of Gadolinium, we question if the use of a chelator may help improve symptoms or worsen them by increasing osmolarity. Lastly, it is not known what the true cross reactivity is between the contrast agents, if any.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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