Intrathecal Baclofen Therapy

Intrathecal Baclofen Therapy

Intrathecal baclofen was first introduced in 1985 to manage childhood hypertonia. There has been an evolution in thought as to how candidates should be identified and what forms of hypertonia respond to this treatment.

Indications

Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord injury and brain injury.

Intrathecal baclofen (ITB) has been known to reduce spasticity which did not respond to oral medications and botulinum toxin treatment.

Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump.

For spasticity of spinal cord origin, ITB Therapy via an implantable infusion system should be reserved for patients unresponsive to oral baclofen or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy.


Berntsson et al., reported the potential beneficial effects of ITB treatment in patients with hereditary ataxia who also suffer from spasticity/spasms 1).

Screening test

A successful trial may confirm predetermined goals, which may include improved mobility/positioning, decreased time/improved independence for activities, less home exercise, better wheelchair tolerance, decreased caregiver time, improved sleep, and reduced pain, or may modify goals and expectations. Individuals should not be tested in the presence of active medical issues (e.g., MS exacerbations, active urinary tract infection, nonhealing wounds). Oral antispasmodics can be weaned before trial if a goal is to eliminate them. The standard baclofen test dose is a 50-mcg bolus, 25 mcg in very small children or patients who rely on spasticity for mobility. Patients unresponsive to the standard dose may require 75 mcg or 100 mcg; 24 hours should elapse between bolus doses. Cardiopulmonary parameters should be checked frequently during the first two hours postinjection, and spasticity measures assessed at least twice within four hours. Observation continues until the patient is stable and recovers from hypertonia. Adverse events include spinal headaches, nausea/vomiting, urinary retention, hypotension, seizures, drowsiness/sedation, respiratory depression, and coma. Before implantation, team members must discuss starting dose, drug concentration, delivery mode, pump size and location, and catheter tip placement. Patients/caregivers should understand the commitment necessary for ITB therapy 2).

Adverse events

Adverse events (AEs) related to intrathecal baclofen (ITB) therapy in adults, was relatively low. This has to be balanced against the clinical, functional and quality of life improvements, which are expected from ITB therapy 3).

This therapy is contraindicated in patients who are hypersensitive to baclofen. Implantation of the infusion system is contraindicated if the patient is of insufficient body size, requires a pump implant deeper than 2.5 cm, or, in the presence of spinal anomalies or active infection.

The most frequent drug adverse events vary by indication but include: hypotonia (34.7%), somnolence (20.9%), headache (10.7%), convulsion (10.0%), dizziness (8.0%), urinary retention (8.0%), nausea (7.3%), and paresthesia (6.7%). Pump system component failures leading to pump stall, or dosing/programming errors may result in clinically significant overdose or underdose. Acute massive overdose may result in coma and may be life threatening.

The most frequent and serious adverse events related to device and implant procedures are catheter dislodgement from the intrathecal space, catheter break/cut, and implant site infection including meningitis. Electromagnetic interference (EMI) and Magnetic resonance imaging (MRI) may cause patient injury, system damage, operational changes to the pump, and changes in flow rate.

Case series

The objective of a study of Berntsson et al., from Sweden was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity.

A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient.

The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment.

They reported the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia 4).

2017

A study aimed to investigate beneficial and adverse effects of Intrathecal Baclofen (ITB) bolus injection and pump therapy in patients with cerebral palsy (CP) and to compare outcomes to patients with acquired brain injury such as traumatic brain injury and cerebral hypoxia. ITB test trials were performed in 37 patients (19 CP and 18 acquired brain injury). Based on ambulatory function, CP patients were divided into 2 groups: 11 patients with nonambulatory CP and 8 patients with ambulatory CP. Change of spasticity was evaluated using the Modified Ashworth Scale. Additional positive or negative effects were also evaluated after ITB bolus injection. In patients who received ITB pump implantation, outcomes of spasticity, subjective satisfaction and adverse events were evaluated until 12 months post-treatment. After ITB bolus injection, 32 patients (86.5%) (CP 84.2% versus acquired brain injury 88.9%) showed a positive response of reducing spasticity. However, 8 patients with CP had negative adverse effects. Particularly, 3 ambulatory CP patients showed standing impairment and 1 ambulatory CP patient showed impaired gait pattern such as foot drop because of excessive reduction of lower extremity muscle tone. Ambulatory CP patients received ITB pump implantation less than patients with acquired brain injury after ITB test trials (P = .003 by a chi-squared test). After the pump implantation, spasticity was significantly reduced within 1 month and the effect maintained for 12 months. Seventeen patients or their caregivers (73.9%) were very satisfied, whereas 5 patients (21.7%) suffered from adverse events showed no subjective satisfaction.

ITB therapy was effective in reducing spasticity in patients with CP and acquired brain injury. Before ITB pump implantation, it seems necessary to perform the ITB bolus injection to verify beneficial effects and adverse effects especially in ambulatory CP 5).

2016

In a single center study Motta et al investigated the complications occurring before and after the introduction of the new Ascenda intrathecal catheter (Medtronic Inc.) in pediatric patients treated with intrathecal baclofen therapy (ITB) for spasticity and/or dystonia.

This was a retrospective review of 508 children who had received ITB, 416 with silicone catheters in the 13 years between September 1998 and September 2011 and 92 with Ascenda intrathecal catheters in the 3 years between September 2011 and August 2014. The authors evaluated major complications such as infections, CSF leaks treated, and problems related to the catheter or pump, and they compared the 2 groups of patients who had received either a silicone catheter or an Ascenda catheter implant. RESULTS One hundred twenty patients in the silicone group (29%) and 1 patient in the Ascenda group (1.1%; p < 0.001) had a major complication. In the silicone group 23 patients (5.5%) were affected by CSF leakage and 75 patients (18%) experienced 82 catheter-related events, such as occlusion, dislodgment, disconnection, or breakage, which required catheter replacement. In the Ascenda group, only 1 patient (1.1%) was affected by CSF leakage. CONCLUSIONS To the authors’ knowledge, this study is the first in the literature to compare the performance of the new Ascenda catheter, introduced in 2011, with the traditional silicone catheter for intrathecal drug infusion. In their analysis, the authors found that the Ascenda catheter can reduce major complications related to the catheter after ITB pump implantation. Further investigation is necessary to expand on and confirm their results 6).

Case reports

The case of a young woman who received intrathecal baclofen therapy (ITB) and subsequently became pregnant and had a normal delivery. A 28-year-old woman with flexion myelopathy had anterior decompression with fusion at C4/5 and C5/6 levels. Clinical symptoms improved after surgery. However, when she was 29 years old, her symptoms steadily advanced to Modified Ashworth Scale 3 spasticity level in the lower legs, with pain in both of them and urinary retention tendency. Since a 25 μg intrathecal baclofen injection improved her symptoms, an ITB pump system was implanted. After surgery, lower limb spasticity and urinary retention improved. Two years after ITB pump implantation, the patient married and became pregnant. The patient intended to have normal delivery but the induction of labor was ineffective and childbirth was completed by Cesarean section with lumbar anesthesia. The infant’s Apgar score was 8 at 1 min and 9 at 5 min, and birth-weight was 2,704 g. We measured the baclofen concentration in the patient’s breast milk using high-performance liquid chromatography/tandem mass spectrometry. The level of baclofen in the breast milk was very low (0.617 ng/ml) and the predicted pharmacological effect on the infant was judged to be negligible. No withdrawal symptoms or muscle tone abnormalities were found after birth. Our findings indicate that ITB therapy could be considered for young women with severe spasticity, even if they plan to have children 7).


A report describes the successful management of painful spasms in a 65-year-old woman with Friedreich’s ataxia (FA) via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments.

To Kalyvas et al., knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, they attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary 8).

References

1) , 4)

Berntsson SG, Gauffin H, Melberg A, Holtz A, Landtblom AM. Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms. Stereotact Funct Neurosurg. 2019 Mar 14:1. doi: 10.1159/000497165. [Epub ahead of print] PubMed PMID: 30870851.
2)

Boster AL, Bennett SE, Bilsky GS, Gudesblatt M, Koelbel SF, McManus M, Saulino M. Best Practices for Intrathecal Baclofen Therapy: Screening Test. Neuromodulation. 2016 Aug;19(6):616-22. doi: 10.1111/ner.12437. Epub 2016 Jul 19. Review. PubMed PMID: 27434115.
3)

Borrini L, Bensmail D, Thiebaut JB, Hugeron C, Rech C, Jourdan C. Occurrence of adverse events in chronic intrathecal baclofen infusion: a one-year follow-up study of 158 adults. Arch Phys Med Rehabil. 2014 Jan 6. pii: S0003-9993(14)00003-3. doi: 10.1016/j.apmr.2013.12.019. [Epub ahead of print] PubMed PMID: 24407102.
5)

Yoon YK, Lee KC, Cho HE, Chae M, Chang JW, Chang WS, Cho SR. Outcomes of intrathecal baclofen therapy in patients with cerebral palsy and acquired brain injury. Medicine (Baltimore). 2017 Aug;96(34):e7472. doi: 10.1097/MD.0000000000007472. PubMed PMID: 28834868.
6)

Motta F, Antonello CE. Comparison between an Ascenda and a silicone catheter in intrathecal baclofen therapy in pediatric patients: analysis of complications. J Neurosurg Pediatr. 2016 Jun 24:1-6. [Epub ahead of print] PubMed PMID: 27341610.
7)

Hara T, Nakajima M, Sugano H, Karagiozov K, Hirose E, Goto K, Arai H. Pregnancy and Breastfeeding during Intrathecal Baclofen Therapy – A Case Study and Review. NMC Case Rep J. 2018 Jun 25;5(3):65-68. doi: 10.2176/nmccrj.cr.2017-0191. eCollection 2018 Jul. PubMed PMID: 30023142; PubMed Central PMCID: PMC6048348.
8)

Kalyvas AV, Drosos E, Korfias S, Gatzonis S, Themistocleous M, Sakas DE. Intrathecal Baclofen Therapy for Painful Muscle Spasms in a Patient with Friedreich’s Ataxia. Stereotact Funct Neurosurg. 2018 Jun 8:1-4. doi: 10.1159/000489220. [Epub ahead of print] PubMed PMID: 29886479.

Dual antiplatelet therapy

Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts 1).

Adequate dual antiplatelet (AP) therapy is imperative when performing neurovascular stenting procedures. Currently, no consensus for the ideal AP regimen exists.

The most frequent included acetylsalicylic acid (ASA) 325 mg+Plavix 75 mg daily (for 7 days prior) and ASA 325 mg+Plavix 75 mg daily (for 5 days prior) for routine placement of intracranial and cervical stents, respectively. For emergency placement, ASA 325 mg+Plavix 600 mg (at time of surgery) was the most frequently used.

Significant heterogeneity in dual antiplatelet regimens following Pipeline Embolization Device (PED) placement and associated costs, exists at major academic neurovascular centers. The most commonly used first line dual antiplatelet regimen consists of aspirin and clopidogrel. Two major alternate protocols involving ticagrelor and prasugrel, are administered to clopidogrel hypo-responders. The optimal dual antiplatelet regimen for patients with cerebrovascular conditions has not been established, given limited prospective data within the neurointerventional literature 2)

Given its importance, evidence based protocols are imperative. Minimal literature exists focusing on neurovasculature, and therefore understanding current practice patterns represents a first step toward generating these protocols. 3).

Case reports

Ravina et al., presented in 2018 a literature review and an illustrative case of an 18-year-old man who presented with progressive headaches and was found to have a large, unruptured basilar apex aneurysm involving the origins of bilateral superior cerebellar artery and posterior cerebral artery. Given the small posterior communicating artery and complexity of the aneurysm, proximal basilar artery occlusion with unilateral superficial temporal artery-to-superior cerebellar artery bypass was recommended. Despite antiplatelet treatment with acetylsalicylic acid pre- and postoperatively, the patient developed acute ischemia of the brainstem and cerebellum as well as an embolic left temporal lobe infarct. The patient received dual antiplatelet therapy starting postoperative day 6 following which he experienced no new infarcts and made a significant neurologic recovery. The current evidence suggests that proximal BA occlusion in complex BA apex aneurysm cases is thrombogenic and can be especially dangerous if thrombosis occurs suddenly in aneurysms without pre-existing intraluminal thrombus. Dual antiplatelet therapy during the first postoperative week presents a possible strategy for reducing the risk of ischemia due to sudden aneurysm thrombosis 4).

1)

Hilkens NA, Algra A, Kappelle LJ, Bath PM, Csiba L, Rothwell PM, Greving JP; CAT Collaboration. Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke. Neurology. 2018 Jan 26. pii: 10.1212/WNL.0000000000004997. doi: 10.1212/WNL.0000000000004997. [Epub ahead of print] PubMed PMID: 29374102.
2)

Gupta R, Moore JM, Griessenauer CJ, Adeeb N, Patel AS, Youn R, Poliskey K, Thomas AJ, Ogilvy CS. Assessment of Dual Antiplatelet Regimen for Pipeline Embolization Device Placement: A Survey of Major Academic Neurovascular Centers in the United States. World Neurosurg. 2016 Sep 15. pii: S1878-8750(16)30839-7. doi: 10.1016/j.wneu.2016.09.013. [Epub ahead of print] PubMed PMID: 27641263.
3)

Faught RW, Satti SR, Hurst RW, Pukenas BA, Smith MJ. Heterogeneous practice patterns regarding antiplatelet medications for neuroendovascular stenting in the USA: a multicenter survey. J Neurointerv Surg. 2014 Jan 3. doi: 10.1136/neurintsurg-2013-010954. [Epub ahead of print] PubMed PMID: 24391160.
4)

Ravina K, Strickland BA, Buchanan IA, Rennert RC, Kim PE, Fredrickson VL, Russin JJ. Postoperative antiplatelet therapy in the treatment of complex basilar apex aneurysms implementing Hunterian ligation and extracranial-to-intracranial bypass: review of the literature with an illustrative case report. World Neurosurg. 2018 Dec 8. pii: S1878-8750(18)32798-0. doi: 10.1016/j.wneu.2018.11.237. [Epub ahead of print] Review. PubMed PMID: 30537547.

Sonodynamic therapy combined with 5-aminolevulinic acid

Suehiro et al., from Matsuyama investigated the antitumor activity of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas to explore the possibility for clinical use of 5-ALA-mediated SDT (5-ALA-SDT).

In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry and TUNEL staining. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined by analysis of the effect of pretreatment with the radical scavenger edaravone. Effects of 5-ALA-SDT with high intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated.

The 5-ALA-SDT inhibited cell growth and changed cell morphology, inducing cell shrinkage, vacuolization, and swelling. Flow cytometric analysis and TUNEL staining indicated that 5-ALA-SDT induced apoptotic cell death in all gliomas. The 5-ALA-SDT generated significantly higher ROS than in the control group, and inhibition of ROS generation by edaravone completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. The proliferative activity of the entire tumor was markedly decreased. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact.

The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field, whereas the surrounding brain tissue remained normal, resulting in longer survival of the HIFU-treated mice compared with that of untreated mice. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas 1).1) Suehiro S, Ohnishi T, Yamashita D, Kohno S, Inoue A, Nishikawa M, Ohue S, Tanaka J, Kunieda T. Enhancement of antitumor activity by using 5-ALA-mediated sonodynamic therapy to induce apoptosis in malignant gliomas: significance of high-intensity focused ultrasound on 5-ALA-SDT in a mouse glioma model. J Neurosurg. 2018 Jan 19:1-13. doi: 10.3171/2017.6.JNS162398. [Epub ahead of print] PubMed PMID: 29350596.

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