Intrathecal Agents Research Articles

Abstract PO-033: Unveiling the complexity of HIV-associated plasmablastic lymphoma: A case report of anal cavity presentation with unconventional immunohistochemical profile

Abstract Introduction: HIV-associated Plasmablastic Lymphoma (PBL) stands as a rare subset of Diffuse Large B-cell Lymphoma (DLBCL), marked as an AIDS-defining malignancy. The primary presentation site is the oral cavity. Although extra-oral PBLs have been reported, these are considered to be very rare. Despite its scarcity, understanding its pathogenesis, diagnosis, and management remains paramount. Herein, we elucidate a distinctive case of HIV-associated PBL manifesting in the anal cavity, an infrequent site, accompanied by an intriguing immunohistochemical signature. Clinical Course: A 30-year-old male presented with symptoms indicative of an anal mass, ultimately diagnosed as Plasmablastic Lymphoma. Further evaluation disclosed a pulmonary nodule and a substantial anal-perineum mass. Given the concurrent HIV infection, initiation of retroviral therapy was crucial alongside lymphoma-directed treatment. Notably, immunohistochemical analysis revealed an unusual profile, encompassing positive expression for CD45, CD38, MYC, OCT2, and MUM1, alongside a heightened Ki-67 proliferation index. Conversely, markers such as CD20, PAX5, Pankeratin, CK7, CK20, MART1, CD30, HHV8 CD138 and P63 exhibited negativity. Epstein-Barr virus (EBV) presence was detected. Treatment initiation comprised HyperCVAD chemotherapy, supplemented by intrathecal chemotherapy and methotrexate. Discussion: Immunophenotypically, PBL conventionally lacks CD45, CD20, and CD79a expression while expressing CD38, CD138, and MUM1. However, our case deviated with positive CD45 expression and negative CD138. Treatment paradigms for HIV-associated PBL encompass intensive regimens such as CHOP-alike regimens with other intensive alternatives such as CODOX-M/IVAC, DA-EPOCH or Hyper-CVAD therapy, with limited intrathecal agent utilization to avert central nervous system involvement. Despite aggressive therapeutic measures, prognosis remains guarded. The progression free survival rates range between 6 and 7 months, with median overall survival falling within the 11 to 13 month range. Long-term survivors predominantly emerge among pediatric patients, underscoring potential disparities in disease biology and treatment response. Conclusion: This case epitomizes the heterogeneity and intricacy inherent in HIV-associated Plasmablastic Lymphoma. The unconventional presentation in the anal cavity, coupled with an atypical immunohistochemical profile, poses challenges to diagnostic and therapeutic strategies. Collaborative efforts with specialized centers are imperative for optimal disease management, accentuating the imperative for sustained research endeavors to enhance outcomes in this aggressive lymphoma variant. Citation Format: Aliya M Khan, Mehmet Hepgur, Sophia Navajas. Unveiling the complexity of HIV-associated plasmablastic lymphoma: A case report of anal cavity presentation with unconventional immunohistochemical profile [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-033.

Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

Brain Metastases and Leptomeningeal Disease.

Central nervous system (CNS) metastases include brain parenchymal, spinal cord, and leptomeningeal metastases. This article discusses the diagnostic and therapeutic advances of the last decade that have improved outcomes for patients with these CNS metastases. The diagnostic tools for CNS metastases, particularly leptomeningeal disease, have evolved over the past decade with respect to advancements in CSF analysis. Multiple medical therapies are now available for brain metastasis treatment that have shown CNS efficacy, including targeted therapies and antibody-drug conjugates. Molecular testing for CNS metastases has become more common and the repertoire of molecularly targeted therapies continues to expand. Advancements in radiation therapy, including improvements in stereotactic radiation techniques, whole-brain radiation with hippocampal avoidance, and proton beam radiation, have changed the radiation management of patients with CNS metastases. New intrathecal agents are currently being tested for the management of leptomeningeal metastases. CNS metastases are far more common than primary brain tumors and are increasing in prevalence in the setting of improved treatments and prolonged survival in patients with systemic cancers. There have been many changes in the diagnostics and treatment of CNS metastases, yielding subsequent improvements in patient outcomes with further advancements on the horizon.

Treatment pattern and outcomes of leptomeningeal carcinomatosis in India – a retrospective study

Leptomeningeal carcinomatosis (LMC), the metastatic spread of cancer to the leptomeninges, is a rare complication and has a dismal prognosis. Due to limited data available on LMC from India, we conducted a country-wise audit of LMC across 15 centres in India. The current study conducted in 2020, was a retrospective, multicentric audit of adult patients (aged ≥18 years) with diagnosis of LMC and who received treatment during 2010-2020. Baseline characteristics, details related to previous treatments, cancer sites, LMC diagnosis, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed, and Kaplan Meier analysis was performed for the estimation of OS. Among the patients diagnosed with LMC (n=84), diagnosis was confirmed in 52 patients (61.9%) and 'probable' in 32 (38.1%) patients. The three most common cause of malignancy were non-small cell lung cancer (NSCLC), breast cancer and gastrointestinal cancer with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients respectively. Intrathecal therapy was offered in 33 patients (39.3%). The most common intrathecal agent was methotrexate in 23 patients (27.4%). The median OS was 90 days (95% CI 48-128). Among tested variables, intrathecal therapy administration (hazard ratio [HR]=0.36, 95% CI 0.19-0.68) and primary in lung (HR=0.43, 95% CI 0.23-0.83) had a favourable impact on OS. Prognosis with leptomeningeal carcinomatosis is poor with a significant burden of morbidity and mortality in India. This data aims to highlight the current outcomes and facilitate further research on LMC. None.

Cerebrospinal fluid-administered therapies for leptomeningeal metastases from solid tumors.

Aims/purpose: Leptomeningeal metastases (LM) are associated with substantial morbidity and mortality. Several approaches are used to treat LM, including intrathecally administered therapies. We consolidated current studies exploring intrathecal therapies for LM treatment. Patients & methods: A review of clinical trials using intrathecal agents was conducted with outcomes tabulated and trends described. 48 trials met the inclusion criteria. Initial investigations began with cytotoxic agents; following this were formulations with longer cerebrospinal fluid half-lives, targeted antibodies and radionucleotides. Results & conclusion: Outcomes were not reported consistently. Survival, when reported, remained poor. Intrathecal therapies for LM remain a viable option. Their use can be informed by an understanding of efficacy, safety and toxicity. They may be an important component of future LM treatments.

Effectiveness and safety of ultra-low-dose spinal anesthesia versus perineal blocks in hemorroidectomy and anal fistula surgery: a randomized controlled trial

BackgroundUltra-low-dose Spinal Anesthesia (SA) is the practice of employing minimal doses of intrathecal agents so that only the roots that supply a specific area are anesthetized. The aim of this study was to compare the effectiveness and safety of ultra-low-dose spinal anesthesia with that of Perineal Blocks (PB). MethodsA two-arm, parallel, double-blind randomized controlled trial comparing two anesthetic techniques (SA and PB) for hemorrhoidectomy and anal fistula surgery was performed. The primary outcomes were postoperative pain, complementation and/or conversion of anesthesia, and hemodynamic changes. ResultsFifty-nine patients were included in the final analysis. The mean pain values were similar in the first 48 h in both groups (p > 0.05). The individuals allocated to the SA group did not need anesthetic complementation; however, those in the PB group required it considerably (SA group, 0% vs. PB group, 25%; p = 0.005). Hemodynamic changes were more pronounced after PB: during all surgical times, the PB group showed lower MAP values and higher HR values (p < 0.05). Postoperative urinary retention rates were similar between both groups (SA group 0% vs. PB group 3.1%, p = 0.354). ConclusionSA and PB are similarly effective in pain control during the first 48 h after hemorrhoidectomy and anal fistula surgery. Although surgical time was shorter among patients in the PB group, the SA technique may be preferable as it avoids the need for additional anesthesia. Furthermore, the group that received perineal blocks was under sedation with a considerable dose of propofol.

Spinal anesthesia in infants undergoing urologic surgery duration greater than 60 minutes

Spinal anesthesia (SA) has been safely utilized in infants. There are limited data regarding the safety and efficacy of SA in pediatric urologic surgery lasting ≥60min. We outlined the perioperative course for infants undergoing single-injection 0.5% plain bupivacaine SA-only for urologic procedures lasting ≥60min. To characterize the safety and efficacy of SA for urologic surgery in infants lasting ≥60min. We reviewed our prospectively maintained database of infants undergoing SA for urologic procedures lasting ≥60min from May 2018 to March 2021. Patients received preoperative intranasal dexmedetomidine, some received intranasal fentanyl, and all patients received lidocaine cream applied preoperatively over the lumbar spine. Oral sucrose on a pacifier was provided as needed, and the patient's arms were swaddled for the procedure. Success was defined as no conversion to general anesthesia. Time points for start/end of spinal injection, procedure duration, wheels in/out of operating room (OR), and discharge were collected. Of 245 cases conducted with SA during the study period, 76 (31%) infants underwent surgery lasting ≥60min. Of these, 73 (96%) were successfully completed with SA alone. In the 3 cases converted to general anesthesia, 2 (67%) required mask anesthesia after 96 and 169min (for the last <10min of surgery), and one was converted to intubation before start of surgery. Median patient age was 6 (IQR 5-7) months, and median procedure length was 95 (IQR 75-120) minutes. Following initial preoperative intranasal dexmedetomidine±fentanyl, at least one additional dose of IV sedative was given in 27 (36%) cases at a median time of 90 (IQR 60-120) minutes into surgery. Following closure, patients exited the OR after a median 10 (IQR 8-12) minutes and subsequently discharged after spending a median of 73 (IQR 61-96) minutes in recovery. We describe pediatric urologic surgical cases lasting ≥60min that employed single-injection intrathecal bupivacaine alone without adjunct intrathecal agents. In this report, SA was safely utilized in infants undergoing urologic procedures lasting at least 60min, with about 40% of patients receiving additional IV dexmedetomidine and fentanyl. Non-medication measures (swaddling, oral sucrose) were important for maximizing patient comfort. Communication between surgeon and anesthesia as cases progress is key to maintaining adequate anesthesia. A single-injection bupivacaine-only spinal anesthesia approach for urologic surgery lasting over an hour and up to 3h is safe and effective in infants. Selecting appropriate candidates for SA should be a joint decision between the surgeon and the anesthesiologist.

Intraventricular haemorrhage due to re-ruptured arteriovenous malformation cleared with tissue plasminogen activator administered through a pre-existing ventriculoperitoneal shunt

In the context in intraventricular haemorrhage (IVH), intrathecal thrombolytic agents administered in conjunction with extraventricular drainage have been demonstrated to clear larger volumes of blood and reduce mortality rates. However, patients with arteriovenous malformations (AVM) have been mostly excluded from clinical trials. We describe a patient with hydrocephalus secondary to a ruptured AVM who was treated via external ventriculostomy, which was subsequently converted to a ventriculoperitoneal shunt (VPS). Eight months later, the AVM re-ruptured, causing IVH and rendering the patient comatose. Taking into consideration the patient’s poor outlook, a single dose of intraventricular tissue plasminogen activator (t-PA) was administered through the shunt reservoir. The shunt maintained its function and the patient's condition ultimately improved. This impressive case demonstrates the utility of t-PA administered through an existing VPS in the setting of IVH due to ruptured AVM, highlighting its lifesaving potential in the appropriate patient and overall decrease in the cost of care by mitigating the need for shunt revision.

Investigation of the histological changes in spinal nerve roots post intrathecal ketamine administration

Background: Ketamine is a general anesthetic agent, administered intramuscularly or intravenously. It is generally used for induction and less frequently for the continuation of surgical anesthesia. Although ketamine was initially thought to be used as an intrathecal agent, psychomimetic side effects were observed. Objectives: In this study, the differences in the spinal nerve roots postintrathecal ketamine injection have been examined in the light and electron microscope. Materials and Methods: 30 min, 1 h, and 24-h postintrathecal ketamine (0.5 mg/kg) injection; the rabbits were sacrificed. The tissue samples taken from the injection area fixed with 1st 2% glutaraldehyde and later 1% OsO4. Following dehydration tissue samples embedded in Araldite and sections were taken and examined in the light and electron microscope. Results: There were severe degenerations in the myelinated nerve fibers postintrathecal injection of ketamine. Fading on the myelin lamellae, shrinking and vacuolization of the axoplasm, endoneurial edema, organelle loss, and cystic parts were observed. The vacuolization and lack of organelles in the Schwann cell cytoplasm were clear. The degeneration of the large myelinated nerve fibers was observed more than unmyelinated fibers. Conclusion: The general and local anesthetics used have significant side effects such as respiratory depression or permanent neurological disorders. Therefore, new options are searched, and the effects of the drugs used in different fields of anesthesia were investigated.

Effectiveness and Safety of Intrathecal Ziconotide: Interim Analysis of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP-). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP- patients, respectively. Mean (SEM) percentage changes in NPRS scores were -29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP- patients (n = 17) at month 6 and -34.4% (9.1%) in FIP+ patients (n = 14) and -3.4% (10.2%) in FIP- patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP- (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP- (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP- patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

The Pharmacology of Spinal Opioids and Ziconotide for the Treatment of Non-Cancer Pain

BackgroundIntrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and outcomes, clinicians are motivated to rethink the traditional spinal infusion pump patient selection criteria and indications. We review the current understanding of the pharmacology of commonly employed intrathecal agents and the clinical relevance.MethodsSearch strategies for data acquisition included Medline database, PubMed, Google scholar, along with international and national professional meeting content, with key words including pharmacology of opioids, intrathecal therapy, ziconotide, pharmacokinetics, and intrathecal drug delivery. The search results were limited to the English language.ResultsOver 300 papers were identified. The literature was condensed and digested to evaluate the most commonly used medications in practice, sto serve as a foundation for review. We review on-label medications: ziconotide and morphine, and off label medications including fentanyl, sufentail, and hydromorphine.ConclusionIntrathecal therapy has level-one evidence for use for malignant pain and nonmalignant pain, with continued cost savings and improved safety. To most effectively serve our patients, a clear appreciation for the pharmacology of these commonly employed medication is paramount..

Primary Hydromorphone-Related Intrathecal Catheter Tip Granulomas: Is There a Role for Dose and Concentration?

Intrathecal drug delivery therapy has been used effectively in treating patients with intractable chronic pain. The development of an intrathecal catheter tip granuloma (ICTG) related to delivery of intrathecal opiates is a relatively infrequent, but potentially devastating complication. While there are many morphine-related ICTG cases described, reports of hydromorphone-related ICTG are limited. In addition, studies suggest a strong correlation between the use of higher doses and concentrations of intrathecal opiates and ICTG formation. The objective of this study is to determine the incidence and the association of intrathecal hydromorphone dose, concentration, duration of treatment and concomitant agents with ICTG formation. This is a retrospective analysis of 101 consecutive patients implanted with intrathecal infusion delivery devices. Data were collected from chart review, and records of pump refills from the division of Pain Medicine of University Hospitals or outsourced to a home pump refill service. From a cohort of 101 consecutively implanted patients, 69 were treated with intrathecal hydromorphone and followed up postimplant for an average of 33.5 ± 24 months (range 0-93 months; 95% CI of 27-39 months). The incidence of ICTG in our patient population was 8.7% during this period of time postimplant with mean time to granuloma detection 35.1 ± 7.9 months. Patients developing granuloma (n = 6) were treated with a combination of intrathecal hydromorphone and bupivacaine infusion. Exposure time to intrathecal agents was not different between the granuloma and nongranuloma group. Monthly dose increase of hydromorphone was higher in granuloma group vs. non-granuloma group (58 ± 34 mcg/month n = 6 vs. 25 ± 8 mcg/month n = 63). Four out of six granuloma cases occurred with low dose and concentration of IT hydromorphone (160-370 mcg/day; 0.75-1.0 mg/mL concentration). Intrathecal bupivacaine dose was not different between groups. A subset of patients was treated with intrathecal fentanyl and bupivacaine. No intrathecal granulomas occurred in this patient cohort. This is the first clinical report demonstrating an association of hydromorphone with intrathecal granulomas, particularly at low doses and concentrations of hydromorphone. This study supports the notion that using low dose of IT opioids might not protect against ICTG development but that the level of exposure and type of opioid used in IT space might be highly correlated with ICTG development. Further research and recommendations related to chronic intrathecal opioid infusions are necessary to raise awareness of significant incidence of ICTG and development of tests to isolate patient populations at high risk.

Clinical Uses of Intrathecal Therapy and Its Placement in the Pain Care Algorithm.

Intrathecal drug delivery is an effective treatment option for patients with severe chronic pain who have not obtained adequate analgesia from more conservative therapies (eg, physical therapy, systemic opioids, nonsteroidal anti-inflammatory drugs, antidepressants, and anticonvulsants). This review focuses on, but is not limited to, the 2 agents currently approved by the U.S. Food and Drug Administration for intrathecal analgesia: preservative-free morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker). We describe the appropriate use of intrathecal therapy in the management of severe chronic pain, based on current best practices. Topics addressed here include patient selection, trialing, dosing and titration, adverse event profiles, long-term management, intrathecal therapy for cancer-related pain, and the placement of intrathecal therapy in the pain care algorithm. In appropriately selected patients with chronic pain, intrathecal therapy can provide substantial pain relief with improved functioning and quality of life. Successful long-term management requires ongoing patient monitoring for changes in efficacy and the occurrence of adverse events, with subsequent changes in intrathecal dosing and titration, the addition of adjuvant intrathecal agents, and the use of concomitant oral medications to address side effects, as needed. Based on an infrequent but clinically concerning risk of overdose, granuloma, and other opioid-induced complications, nonopioid therapy with ziconotide may be preferred as a first-line intrathecal therapy in patients without a history of psychosis or allergy.

Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats.

To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence.

Diagnosis of nerve root avulsion injuries in adults with traumatic brachial plexopathies: MRI compared with CT myelography

Background: Computed tomography myelography (CTM) has been broadly adopted as the ‘gold standard’ imaging technique in the diagnosis of nerve root avulsion injuries in traumatic brachial plexopathies. CTM has the distinct advantage of better spatial resolution than magnetic resonance imaging (MRI); however, this technique is invasive and can result in significant patient discomfort. MRI, therefore, seems relatively more advantageous as it is less invasive (requires no lumbar puncture), lacks radiation exposure, has no adverse reactions related to intrathecal contrast agents and confers excellent soft-tissue contrast. Objectives: To compare the sensitivity and specificity of MRI with CTM in the diagnosis of preganglionic nerve root avulsion injuries in adults with traumatic brachial plexopathies at the Inkosi Albert Luthuli Central Hospital.Method: A retrospective comparative analysis was performed on 16 adult patients with traumatic preganglionic brachial plexopathies who underwent both MRI and CTM at Inkosi Albert Luthuli Central Hospital. Radiologists experienced in both CTM and MRI interpreted the data and a comparison was made using CTM as the gold standard. Results: The sensitivity and specificity for MRI detecting preganglionic nerve root avulsion injuries and pseudomeningoceles was 82% and 100% respectively. The interobserver agreement between CTM and MRI for the detection of preganglionic nerve root avulsion injuries was 81.25% (Kappa = 0.77) and 87.5% (Kappa = 0.84) for the detection of pseudomeningoceles. Conclusion: MRI was as sensitive as CTM at detecting preganglionic nerve root avulsion injuries and pseudomeningoceles of spinal nerve roots C7–T1 of the brachial plexus. Some mild discrepancies existed at the C5 and C6 nerve root levels. Owing to the invasiveness of the procedure and resultant patient discomfort, CTM should be reserved for complicated cases or for patients with contraindications to MRI.

Ziconotide Combination Intrathecal Therapy for Noncancer Pain Is Limited Secondary to Delayed Adverse Effects: A Case Series With a 24-Month Follow-Up.

The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients. A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months. Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months. A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Introduction: Intractable pain

The problem of surgical pain management remains one of the most daunting in our specialty. Traditionally, we divide the surgical approaches into the more historic destructive procedures (“ablative”) and the more contemporary modulatory ones (stimulation or intrathecal agents). The advent of “evidence-based medicine” has caused us to reanalyze the evidentiary basis of everything we do in neurosurgery, and pain procedures are no exception. What this has taught us is that the evidence to support destructive procedures is almost uniformly absent, although reanalysis using contemporary standards has shown that procedures, such as anterolateral cordotomy, may have a justifiable role in pain control, especially for pain associated with cancer. These same standards of evidence have also revealed weakness in the data supporting neuromodulation, particularly neurostimulation. There is some qualified support for spinal cord stimulation based on reasonably conducted prospective trials, although even these studies are flawed. There is almost no indication that deep brain stimulation was ever effective for pain control, as indicated by a structured review using modern criteria. Peripheral nerve stimulation seems to be flourishing in pain centers worldwide, and yet the data to support this method for a variety of diagnoses are lacking. We are currently in an era in which high-quality evidence to support our surgical endeavors will be increasingly important. With this evidence, it is likely that certain procedures, and perhaps whole fields, will disappear. Our hope is that this issue of Neurosurgical Focus will highlight some of the innovative work that is going on in our field and address some of the challenges of gathering and analyzing the data that will keep the area of pain surgery a vibrant and compelling practice for the future. We are grateful to all of the authors for their contributions to this issue as well as the editors and staff of Neurosurgical Focus for their diligent efforts in support of this cause. (http://thejns.org/doi/abs/10.3171/2013.7.FOCUS13277)

Factors That Might Impact Intrathecal Drug Delivery (IDD) Dose Escalation: A Longitudinal Study

Intrathecal drug delivery (IDD) system with implantable pumps has been used to treat cancer-related pain as well as noncancer-related chronic pain. Opioids, including morphine and hydromorphone, are the most commonly used intrathecal (IT) agents. Although technology, techniques, and knowledge of IDD have improved, dose escalation occurs relatively rapidly in noncancer pain. Retrospective chart review of IDD pump patients, implanted for a minimum of 2years, was designed to investigate possible existing predictors that might impact IDD dose escalation, such as patient's demographic risk factors, duration of the treatment, and diagnosis of the patient's pain correlates with increase in medication requirement. Primary outcome was defined as the annual percent escalation in daily opioid dosage, and secondary outcome was the average annual percent reduction in VRS pain scores. Median dosage escalation was 17% per year for patients with neuropathic pain compared with 12% per year for patients with other pain modalities. Mean opioid dosage increased 30.4% more rapidly for patients with neuropathic pain than for other pain modalities. The adjusted difference in means was 28.8% (P=0.001). None of the secondary exposures were statistically significant after the Bonferroni adjustment. No association was found between pain modality and annual percent change in VRS pain score. Annual increases in daily opioid dosage were higher among patients with neuropathic pain than among patients with other modalities; we also found no evidence of difference in annual pain reduction.

Polyanalgesic Consensus Conference 2012

The need for guidance in the use of intrathecal drug administration is critical, as this is a complex and growing field of medicine. Issues include the safest and most effective methods of administering intrathecal agents based upon animal neurotoxicity data, human safety data, and the currently available efficacy data. In some instances, data helpful for creating a perfect treatment algorithm are lacking. The purpose of the Polyanalgesic Consensus Conference (PACC) is to critically evaluate currently available data, to use clinical expertise to fill the gaps in high quality evidence, and to provide guidance to health-care providers using intrathecal drug administration.

Leptomeningeal Metastases

Leptomeningeal cancer dissemination is a metastatic complication with growing impact in clinical oncology. Advances in treatment have been hampered by difficulties in diagnosis and response assessment, and nihilistic attitudes of physicians due to the poor prognosis, even when treating patients. However, relevant advances in therapeutic management have been achieved. In selected patients, survival and time to neurological progression can be improved with therapy, although an early diagnosis is critical (hence the importance of a high suspicion index). It is mandatory to perform an MRI of the entire neuraxis and cerebrospinal fluid (CSF) examination of up to two samples if the first lumbar puncture is negative, with appropriate volume and processing methods. It is advisable to supplement CSF analysis using flow cytometry techniques and new biomarker determinations (not yet validated) to improve diagnostic yield sensitivity. Currently, patients with good performance status and the option to receive effective systemic treatment must be treated with added intrathecal chemotherapy through Ommaya reservoirs and focal radiotherapy to bulky lesions or refractory painful areas. However, a standard treatment approach is not well-established due to the lack of well-designed randomized clinical trials and the mix of different cancer subtypes treated with the same drug in most studies. Liposomal cytarabine offers some advantages over methotrexate, both being first-line treatments for intrathecal administration. Recently, new agents have proven safe and feasible, broadening the available treatment options. The individualized choice of intrathecal agent based on the primary malignancy and appropriate treatment of underlying systemic disease are critical to improved outcomes in these patients.