Morphologic Effects of Glycerol

Glycerol is a trivalent alcohol normally present in human tissue, where it forms the skeleton of the triglycerides, among other functions.^17,18 Glycerol readily penetrates cell membranes and seems to possess distinct cryoprotective properties beneficial to cells. Its toxicity is low, and comparatively high doses must be injected systemically or intrathecally to induce toxic effects.^19,20 Glycerol’s neurolytic action is thought to be due to its hypertonicity, a condition known to injure nerve fibers, especially thin, unmyelinated, and myelinated fibers.²¹ Although the myelin sheath of the coarse fibers gives some transitory protection from this effect, length of exposure, neuron type, and the presence of previous demyelination may be important determinants of the vulnerability of individual fibers. For example, with longer exposures, Robertson²² and Pal and colleagues²³ observed that myelinated fibers were particularly vulnerable, and the degree of damage positively correlated with fiber diameter.

Studies on isolated animal nerve fibers show morphologic changes after exposure to glycerol. These consist of disruption of the tight junction between the Schwann cells and the axolemma, without damage to the axon proper.²⁴ Bathing the fibers in glycerol initially causes the axons to shrink, with a return to basal volume after equilibration of the substance over the cell membranes. With transfer to iso-osmotic conditions, the fibers swell markedly before returning to their normal volume. Thus, marked structural changes are observed with glycerol administration, but the conduction properties of the treated nerve axons remain intact.²⁴

After intraneural and perineural injection of glycerol, Håkanson²⁵ and Rengachary and associates²⁶ observed axolysis with marked myelin sheath swelling. The coarse myelinated fibers sustained the most severe damage, whereas the small-diameter myelinated and unmyelinated fibers are relatively well preserved.²³ In contrast, Bremerich and Reisert²⁷ found only slight histomorphologic changes after glycerol injection in the region of the foramen ovale in the rat in their long-term (180 days) comparative study of axonal damage after injection of glycerol, phenol-glycerol, and saline. A more recent study in dogs submitted to glycerol injection in a single trigeminal ganglion²⁸ demonstrated axonolysis both in myelinated as well as in nonmyelinated fibers.

The damage following glycerol injection into a cavity with isotonic body fluid is probably considerably less severe than perineural deposition. However, Lunsford and associates⁹ observed extensive areas of myelin degradation and axonal swelling in cats subjected to retrogasserian glycerol injections 4 to 6 weeks earlier.

The site of glycerol effects has been specifically studied by Stajcic,²⁹ who injected ³H-labeled glycerol into peripheral branches of the maxillary nerve and in the infraorbital canal of rats. The amount of radioactivity detected in the nerve distal to the foramen rotundum, as well as in the ipsilateral and contralateral gasserian ganglion, was less than 0.1% in all specimens. The author concluded that a retrograde transport mechanism behind the effect is improbable and that the beneficial effect of glycerol occurs at the site of injection.

There is as yet no publication of an autopsy series of patients with TN treated by retrogasserian glycerol rhizolysis. Sweet¹¹ provides an anecdotal description of a patient undergoing a retrogasserian glycerol injection of the extreme volume of 1.5 ml, with subsequent development of anesthesia dolorosa. At a posterior fossa craniotomy “many months” later, the trigeminal rootlets were found to be markedly atrophic.

Neurophysiologic Changes after Glycerol Application

It is likely that the change in osmolarity causes the damage to nerve axons, and the morphologic changes seem to be minimized by a gradual alteration in the osmolarity (e.g., by slowly instilling and removing glycerol from the compartment housing the axons). The functional consequences of glycerol application to normal and damaged nervous tissue are known only fragmentarily, but there are a few observations that might apply to the clinical use of the substance.

Burchiel and Russel³⁰ studied the effect of glycerol on normal and damaged nerves in a rat neuroma model. The neuromas, produced by sectioning of the saphenous nerve, were mechanosensitive and discharged both spontaneously and in response to light manipulation. These researchers found evidence supporting the view that glycerol exerts its major action on the large-diameter fibers. Exposure of the injured nerve to glycerol induced a short episode of increased spontaneous firing in the nerve, a response shown to originate from the myelinated fibers.

The observation by Rappaport and associates³¹ that glycerol injected into neuromas was more effective than alcohol in decreasing autotomy in rats suggests that autotomy may be related to unpleasant “tic-like” paresthesias. The therapeutic mechanism, according to these investigators, could be suppression of ectopic impulse barrage from the neuroma.

Sweet and co-workers³² found that glycerol injected into the trigeminal cistern of patients abolished the late components (corresponding to A-delta and C fibers) of trigeminal root potentials recorded with electric stimulation of the surface of the cheek. These recordings were made only minutes after the injection, and therefore do not permit conclusions concerning long-term effects.

Hellstrand and colleagues (unpublished data; see Håkanson²⁵) studied the effects of glycerol both on isolated frog nerve and on trigeminal root fibers after cisternal injection in the cat. They observed a severe reduction of the evoked potentials with glycerol but a nearly total restoration after rinsing the compartment with saline. This recoverability probably has a bearing on clinical effects and must be taken into account when interpreting the short-term observations of Sweet and associates³² referred to previously. Based on knowledge that glycerol requires at least 30 minutes to equilibrate across a membrane of a living cell and according to the aforementioned experimental observations, evacuation of the glycerol from the cistern after a short time (e.g., 5 to 20 minutes^10,33,34) might induce more severe damage, especially to fine fiber systems, than a slow unloading by diffusion into the subarachnoid space.

Longer-term observations of trigeminal evoked potentials have been reported by Bennett and Lunsford,³⁵ who investigated patients before and 6 weeks after trigeminal glycerol rhizolysis. They confirmed the earlier findings of Bennett and Jannetta³⁶ that thresholds were elevated and evoked potentials had a markedly increased latency on the affected side compared with the healthy one. An additional, unexpected finding was that these aberrations were “normalized” after glycerol rhizolysis. Because partially demyelinated fibers are known to conduct with a slower velocity and at a lower rate,^37,38 they interpreted this finding to indicate that glycerol selectively attacked partially damaged trigeminal axons and, after their elimination, the evoked trigeminal potentials appeared “normalized.”

Further long-term observations were supplied by Lunsford and colleagues,⁹ who noted the most marked changes in trigeminal evoked potentials in cats in the large-diameter myelinated fibers, with additional changes noted as late as 6 weeks after the injection.

Quantitative sensory testing using von Frey hairs, mechanical pulses, and the Marstock technique³⁹ also corroborates the notion that glycerol acts mainly on the large myelinated fiber spectrum.⁴⁰ Eide and Stubhaug⁴¹ examined thresholds for tactile and temperature stimuli in patients with TN before and after glycerol rhizolysis. They found evidence that pain relief after glycerol treatment involved normalization of previously abnormal temporal summation phenomena with little accompanying sensory loss. Kumar and associates⁴² found postinjection quantitative abnormalities of the blink reflex that correlated with sensory impairment.

Thus experimental and clinical observations indicate that the effects of glycerol may be due to its hyperosmolarity and that the rate of alteration of osmolarity is critical for the effect. Furthermore, there are indications that the major part of the effect is exerted through actions on large myelinated fibers, notably those with previous damage to the myelin sheath, thereby possibly affecting the “trigger mechanism” for pain paroxysm. Glycerol has also been reported to downregulate central neuronal hyperexcitability, often without signs of significant additional nerve damage.⁴¹

Preoperative Evaluation

The preoperative evaluation should be focused on the presence of typical signs of TN, previous treatments, the pharmaceutical regimen, the presence of sensory deficits, constant pain components, and ipsilateral hearing loss. Because we recommend the use of contrast medium injection in all cases, intolerance to iodine and previous adverse reactions to contrast medium should be determined. A magnetic resonance imaging study (MRI) with a sequence optimized for the detection of possible neurovascular conflicts, or at least a computed tomography scan with and without contrast injection, should be performed before surgery. The surgeon must evaluate the patient before the procedure to individualize premedication and describe the details of the procedure to the patient to ensure good cooperation during its performance. Most patients tolerate the procedure well in local anesthesia with adequate premedication and with only slight sedation (see Technique section), but very anxious patients may require general anesthesia.

Anesthesia and Sedation

Until the late 1990s, retrogasserian glycerol rhizolysis was performed in a radiographic suite with the patient awake and premedicated approximately 45 minutes before the start of the session with 5 to 10 mg of subcutaneous morphine hydrochloride-scopolamine and 2.5 mg of intramuscular droperidol. The doses were adjusted according to the age and condition of the patient. In some cases, 0.5 mg of atropine was given intravenously immediately before the procedure to prevent bradycardia during needle insertion. An intravenous line with slow infusion of Ringer’s solution is maintained during and for some hours after the session.

Our current protocol involves sedation with intravenous propofol using a syringe pump. No intubation is required and oxygen is supplied via a nasal catheter. In anxious cases a low oral dose of benzodiazepine is given 1 hour preoperatively. The legs are wrapped or compression stockings applied to counteract blood pressure decrease in the semisitting position. General anesthesia and endotracheal intubation are used only in particularly anxious patients. If used, it is important that the anesthesia be terminated with the patient in the sitting position with his head flexed according to the surgeon’s instructions.

The skin at the point of needle insertion and the underlying soft tissue are infiltrated with local lidocaine 0.5%.

Positioning

Since the mid-1990s, a modified dentist’s operating chair has been used in the surgical theater in conjunction with a standard C-arm fluoroscopic image intensifier with image-storing capacity, which provides sufficient picture quality for the clinical procedure.

In most cases, fluoroscopy with lateral projection is used when the cistern is punctured. Further guidance is obtained by switching to the anteroposterior projection. In difficult cases in which entering the proper part of the oval foramen is a problem, the patient’s head may be extended and rotated 15 to 20 degrees from the affected side, and the fluoroscopy arm tilted to give an axial-oblique projection of the skull base including the foramen ovale. With some older equipment, it might be difficult to readily identify the proper foramen on the fluoroscopy monitor. If one needle has already penetrated the foramen, the identification should be easy, and a new needle can readily be inserted in the desired (often medial) part of the foramen.

Trigeminal Cisternography

The technique we use is essentially the same as that described by Håkanson,⁴⁸ although estimation of the cisternal volume is of less importance for deciding what volume of glycerol to inject. The contrast medium must be water soluble, with high radiographic attenuation and low toxicity, and must have a higher specific gravity than CSF. The contrast medium used since 1986 is iohexol (300 mg iodine/ml).⁴⁹ Approximately 0.3 to 0.6 ml is injected with the patient sitting with his or her head slightly flexed to retain as much of the medium in the cistern as possible. If intermittent fluoroscopy is used during injection, the position of the needle tip may be estimated immediately, but it should always be confirmed by radiography in both the lateral and anteroposterior projections. The typical appearance of the trigeminal cistern is illustrated in Fig. 123-3. Ideally, the sensory root filaments (and sometimes the motor portion) should be visualized by lateral cisternography, leaving no doubt about the intracisternal position of the tip. The typical 45-degree medial tilt of the cistern should be seen from the anteroposterior view (Fig. 123-3B). The appearance of the cistern may vary considerably between patients, and it is essential that the surgeon be familiar with this anatomy. Furthermore, there is a subdural-extracisternal compartment in Meckel’s cave that may be injected with contrast medium (Fig. 123-4). This usually happens when contrast medium is injected without prior spontaneous CSF drainage, or if the needle is dislodged from the intracisternal position during injection.

FIGURE 123-3 The typical appearance of the trigeminal cistern filled with contrast medium in the lateral (A) and anteroposterior projections (B). Note the root fibers (A) that give the cistern its striped texture. In the lateral projection (C), there is also sparing of contrast, which indicates the position of the trigeminal motor root (arrow).

FIGURE 123-4 Schematic picture of the different compartments in Meckel’s cave. The arachnoid is drawn with a wavy line. Note the sites (^∗) where extracisternal deposits of contrast medium and glycerol may be performed.

(From Pauser G, Gerstenbrand F, Gross D, eds. Gesichtsschmerz, Schmerzstudien Z. New York: Verlag; 1979, with permission.)

Specific Difficulties

Spontaneous CSF drainage from the needle does not guarantee an intracisternal tip location. In fact, if the cannula is placed a few millimeters too lateral, the tip may be located in the subtemporal subarachnoid space, and a flow of CSF will still be produced. Subsequent cisternography solves this problem. Figure 123-5A shows the proximity of the cisternal and subtemporal subarachnoid compartments in the anteroposterior projection. Figure 123-5B and C illustrate a pure subtemporal contrast injection. Our strategy in this case is to leave the first needle in place and to introduce a second needle using the first one for guidance (Fig. 123-6A and B). It cannot be overemphasized that spontaneous CSF drainage is required before contrast injection. If, in such a case, the contrast medium is injected without fulfilling this requirement, the glycerol may be deposited in the extra-arachnoid, subdural compartment as shown above (see Fig. 123-4).

FIGURE 123-5 The anteroposterior roentgenogram (A), with both the trigeminal cistern and the subtemporal space injected with contrast medium, illustrates the proximity of these two compartments. Medially, the contrast-filled cistern (arrow) is seen barely pierced in its lateral margin by one of the needles. Injection of contrast medium through the lateral needle yielded a filling of the subtemporal space (arrow) instead. The lateral roentgenogram (B), shows a pure subtemporal contrast injection. C, Subtemporal outflow of contrast medium in the anteroposterior projection is shown. No contrast filling of the cistern was obtained, although exit of cerebrospinal fluid from the needle was noted.

FIGURE 123-6 The schematic figure (A) illustrates that because the foramen ovale is a fulcrum point, the needle entry site determines the intracranial destination of the needle tip. A too lateral puncture site produces a medial tip position. An entry that is too medial results in placement of the needle lateral to the trigeminal cistern (c). A puncture site that is too lateral produces a medial tip position (a). The adequate entry is shown by the track (b). (From Jho HD, Lunsford LD. Percutaneous retrogasserian glycerol rhizotomy. Neurosurg Clin North Am. 1997;8:63-74, with permission.) B, The anteroposterior roentgenogram demonstrates the penetration of the foramen with three needles. Contrast injection via the most medial, only, produces cistern filling.

Another problem may arise if the patient’s head is not adequately tilted forward during the injection, because the contrast medium then flows out the porus trigemini and escapes to the posterior fossa, with insufficient cisternal filling to confirm the correct position of the needle tip (Fig. 123-7). This situation may also result in an underestimation of the cisternal volume.