Cerebrospinal Fluid Removal for Idiopathic Intracranial Hypertension: Less Cerebrospinal Fluid Is Best.

BACKGROUND: Although lumbar punctures (LPs) are used for diagnostic evaluation in idiopathic intracranial hypertension (IIH), they can also provide relief from IIH-associated headache. Conversely, low-pressure headache secondary to LP can be debilitating. Low-volume cerebrospinal fluid (CSF) removal to a "high-normal" closing pressure (CP), approximately 18-20 cm H2O, may result in relief of IIH-associated headache with a lowered frequency of post-LP headache. METHODS: We conducted a single-center retrospective analysis from 2011 to 2016 of patients who underwent fluoroscopic LPs aiming for high-normal CPs. Inclusion criteria were as follows: 1) pre-existing diagnosis of IIH, or opening pressure (OP) and clinical findings diagnostic for IIH; 2) height and weight recorded within 1 year; 3) documented LP data parameters; and 4) one week post-LP follow-up documenting whether headache was worse, unchanged, or better. RESULTS: One hundred forty-six patients met the inclusion criteria. Mean age was 34.9 years ± 11.0, and mean body mass index was 39.2 kg/m ± 10.5. Mean volume removed was 9.7 mL ± 4.6. The mean CP was 17.9 cm H2O ±2.7. The mean pressure change (OP-CP) per volume removed was 1.50 cm H2O/mL ±0.6. Headache symptoms at follow-up were improved in 64% (80/125) of patients, worse in 26% (33/125), and unchanged in 10% (12/125). Eleven patients were headache-free, and 11 patients required hospital care for post-LP headache. CONCLUSIONS: Low-volume CSF removal to approximately 18 cm H2O resulted in relief of IIH-associated headache in most patients and a low incidence of post-LP headache. Although clinically variable, these data suggest that for every 1 mL of CSF removed, the CP decreases approximately 1.5 cm H2O.

Radicular Pain Syndromes: Cervical, Lumbar, and Spinal Stenosis.

Back pain is a top primary and urgent care complaint; radicular pain can be caused by herniation of the nucleus pulposus (intervertebral disc), spinal stenosis, or degenerative changes to the vertebrae. The focus of this clinical review will be the clinical approach and treatment of lumbar radicular pain, cervical radicular pain, and spinal stenosis. Usually localized through neurological history, exam, and imaging, specific signs and symptoms for lumbar radicular, spinal stenosis, and cervical radicular pain can help determine etiology. Once radicular back pain has been diagnosed, a multitude of treatment options are available from rest and physical therapy to medications, epidurals, and surgery. The most common and accepted are reviewed. With accurate diagnosis, safe and effective pain management can be employed to shorten radicular episodes and manage recurrent or chronic radicular syndromes. Using a step-wise approach from diagnosis to conservative therapy to potential surgery, radicular pain syndromes can improve or resolve, and patients may achieve a better functional status and quality of life.

Urgent care peripheral nerve blocks for refractory trigeminal neuralgia.

OBJECTIVE: After medication failure, patients with refractory trigeminal neuralgia (TGN) often present urgently and seek more potent or invasive therapies such as opioids or surgical options. Peripheral nerve blocks, safe and simple, may offer extended pain relief prior to opioid use or more invasive ganglion level procedures. METHODS: We report a retrospective case-series (urgent care, at a large urban medical center, over a 2 year period) of nine patients with intractable primary TGN who underwent peripheral trigeminal nerve blocks after failing conservative medical therapy. After antiseptic skin preparation, a 30 g needle was inserted localizing to the supraorbital, infraorbital, and mental foramens. 0.5 mL of 0.25% bupivicaine:1% lidocaine was injected locally at all three foramens. Then, 1 mL of the above was injected in the region of the auriculotemporal nerve (see Video 1). All injections were done on the side with TGN pain. RESULTS: All nine patients experienced immediate pain relief of >50% with 7 of 9 being completely pain free or just mild paresthesia. Six of nine patients had lasting pain relief (1-8 months); three patients reporting pain now tolerable with adjunct medication and two patients were completely pain free. CONCLUSIONS: The treatment paradigm for TGN remains unclear when a patient fails conservative medical therapy. In this case series, many patients achieved rapid and sustained TGN pain relief with peripheral trigeminal nerve blocks. This modality should be considered as a potential therapeutic option in the ED or urgent care setting.

Cerebellar stroke presenting with isolated dizziness: Brain MRI in 136 patients.

OBJECTIVE: To evaluate occurrence of cerebellar stroke in Emergency Department (ED) presentations of isolated dizziness (dizziness with a normal exam and negative neurological review of systems). METHODS: A 5-year retrospective study of ED patients presenting with a chief complaint of "dizziness or vertigo", without other symptoms or signs in narrative history or on exam to suggest a central nervous system lesion, and work-up included a brain MRI within 48h. Patients with symptoms commonly peripheral in etiology (nystagmus, tinnitus, gait instability, etc.) were included in the study. Patient demographics, stroke risk factors, and gait assessments were recorded. RESULTS: One hundred and thirty-six patients, who had a brain MRI for isolated dizziness, were included. There was a low correlation of gait assessment between ED physician and Neurologist (49 patients, Spearman's correlation r2=0.17). Based on MRI DWI sequence, 3.7% (5/136 patients) had acute cerebellar strokes, limited to or including, the medial posterior inferior cerebellar artery vascular territory. In the 5 cerebellar stroke patients, mean age, body mass index (BMI), hemoglobin A1c, gender distribution, and prevalence of hypertension were similar to the non-cerebellar stroke patient group. Mean LDL/HDL ratio was 3.63±0.80 and smoking prevalence was 80% in the cerebellar stroke group compared to 2.43±0.79 and 22% (respectively, p values<0.01) in the non-cerebellar stroke group. CONCLUSIONS: Though there was preselection bias for stroke risk factors, our study suggests an important proportion of cerebellar stroke among ED patients with isolated dizziness, considering how common this complaint is.

Gabapentin in Headache Disorders: What Is the Evidence?

OBJECTIVE: Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of pain, including headache disorders. Off-label GBP is used in headache disorders with some success, some failure, and much debate. Due to this ambiguity, a clinical evidence literature review was performed investigating GBP's efficacy in headache disorders. METHODS: Bibliographic reference searches for GBP use in headache disorders were performed in PUBMED and OVID Medline search engines from January 1, 1983 to August 31, 2014. Based on abstracts read by two reviewers, references were excluded if: GBP was not a study compound or headache symptoms were not studied. The resulting references were then read, reviewed, and analyzed. RESULTS: Fifty-six articles pertinent to GBP use in headache disorders were retained. Eight headache clinical trials were quality of evidence Class 2 or higher based on American Academy of Neurology criteria. Seven of the eight clinical trials showed statistically significant clinical benefit from GBP in various headache syndromes (though modest affects at times). One study, Mathew et al., had concerns about intention-treat analysis breaches and primary outcomes. CONCLUSION: Despite the conflicting evidence surrounding select studies, a significant amount of evidence shows that GBP has benefit for a majority of primary headache syndromes, including chronic daily headaches. GBP has some efficacy in migraine headache, but not sufficient evidence to suggest primary therapy. When primary headache treatments fail, a GBP trial may be considered in the individual patient.

Pharmacotherapy for Spine-Related Pain in Older Adults.

As the population ages, spine-related pain is increasingly common in older adults. While medications play an important role in pain management, their use has limitations in geriatric patients due to reduced liver and renal function, comorbid medical problems, and polypharmacy. This review will assess the evidence basis for medications used for spine-related pain in older adults, with a focus on drug metabolism and adverse drug reactions. A PubMed/OVID search crossing common spine, neck, and back pain terms with key words for older adults and geriatrics was combined with common drug classes and common drug names and limited to clinical trials and age over 65 years. The results were then reviewed with identification of commonly used drugs and drug categories: nonsteroidal anti-inflammatories (NSAIDs), acetaminophen, corticosteroids, gabapentin and pregabalin, antispastic and antispasmodic muscle relaxants, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tramadol, and opioids. Collectively, 138 double-blind, placebo-controlled trials were the focus of the review. The review found a variable contribution of high-quality studies examining the efficacy of medications for spine pain primarily in the geriatric population. There was strong evidence for NSAID use with adjustments for gastrointestinal and renal risk factors. Gabapentin and pregabalin had mixed evidence for neuropathic pain. SNRIs had good evidence for neuropathic pain and a more favorable safety profile than TCAs. Tramadol had some evidence in older patients, but more so in persons aged < 65 years. Rational therapeutic choices based on geriatric spine pain diagnosis are helpful, such as NSAIDs and acetaminophen for arthritic and myofascial-based pain, gabapentinoids or duloxetine for neuropathic and radicular pain, antispastic agents for myofascial-based pain, and combination therapy for mixed etiologies. Tramadol can be well tolerated in older patients, but has risks of cognitive and classic opioid side effects. Otherwise, opioids are typically avoided in the treatment of spine-related pain in older adults due to their morbidity and mortality risk and are reserved for refractory severe pain. Whenever possible, beneficial geriatric spine pain pharmacotherapy should employ the lowest therapeutic doses with consideration of polypharmacy, potentially decreased renal and hepatic metabolism, and co-morbid medical disorders.

Acetaminophen (paracetamol) is safe in older adults, but non-steroidal anti-inflammatories (e.g. ibuprofen) may be more effective for spine-related pain. Non-steroidal anti-inflammatories should be used in short-term lower dose courses with gastrointestinal precaution. Corticosteroids have the least evidence for treating nonspecific back pain. Gabapentin and pregabalin may cause dizziness or difficulty walking, but may have some benefit for neck and back nerve pain (e.g. sciatica) in older adults. They should be used in lower doses with smaller dose adjustments. Some muscle relaxants (carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine) are avoided in older adults due to risk for sedation and falls. Others (tizanidine, baclofen, dantrolene) may be helpful for neck and back pain, with the most evidence for tizanidine and baclofen. These should be used in reduced doses, avoiding tizanidine with liver disease and reducing baclofen dosing with kidney disease. Older antidepressants are typically avoided in older adults due to their side effects, but nortriptyline and desipramine may be better tolerated for neck and back nerve pain at lower doses. Overall, newer antidepressants (namely duloxetine) have a better safety profile and good efficacy for spine-related nerve pain. Tramadol may be tolerated in older adults, but has risk for sedation, upset stomach, and constipation. It may be used in lower doses after alternative medications have failed, and works well with co-administered acetaminophen. Opioids are avoided due to their side effects and mortality risk, but low-dose opioid therapy may be helpful for severe refractory pain with close monitoring of patients clinically.

Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells.

Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood-brain barrier (BBB) drug transporters (P-glycoprotein; P-gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in-vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P-gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co-incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P-gp activity. P-gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P-gp immunoreactive protein in a concentration-dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 microM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P-gp protein increased 2-fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P-gp immunoreactive protein was observed (Spearman r2 = 0.77, P < 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration-dependent increase in P-gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.

Triptans and migraine: advances in use, administration, formulation, and development.

INTRODUCTION: Recent triptan development has focused on new administration methods and formulations, triptan combination therapies, treatment in menstrually related migraines, and novel serotonin receptor subtype agonists (5HTf). Areas covered: Clinical triptan research related to migraine was reviewed, analyzing EMBASE and PUBMED data bases from 01/01/2011 to 06/29/2016, with a focus on clinical trials of class 1 or 2 level of evidence. There have been advances in drug combination therapies, as well as administration devices that aid in ease of use, increase efficacy, and decrease adverse reactions. Some new agents and devices have similar or less efficacy compared to previous generic triptan formulations. New agents have action at the 5HTf receptor subtype, and avoid vascular side effects of classic 5Ht1b/d agonists, however adverse reactions may limit their clinic use. Long half-life triptans, frovatriptan and naratriptan, do appear to have good benefit in menstral related migraine. Expert opinion: Recent advances in triptan development can offer some advantages to migraine therapy and patient preferences, but have a much higher cost compared to individual generic triptan agents. In the coming years, triptan advances with high efficacy, limiting ADRs and cost are welcomed, in this regard the 5HT1b/d triptans are already well established.

Practical considerations in opioid use for brain neoplasm.

Neurologists are often on the front lines of diagnosis for primary and metastatic brain tumors. Patients with brain tumors typically have multiple comorbidities and pain generators beyond headache, necessitating opioid therapy. Opioid-based pain relief and safety in the medically ill patient are complex. While using the lowest-potency opioid with adjunct medications is always prudent, patients with brain tumors frequently require dose escalation. Opioid selection and use is based on the patient's respiratory and cardiac function as well as drug clearance capability. Specific opioid combinations, employing long-acting and short-acting drugs, have greater efficacy in specific patient profiles and make adverse drug reactions, toxicity, abuse, and diversion less likely.

Gabapentin Therapy in Psychiatric Disorders: A Systematic Review.

OBJECTIVE: Gabapentin is commonly used off-label in the treatment of psychiatric disorders with success, failure, and controversy. A systematic review of the literature was performed to elucidate the evidence for clinical benefit of gabapentin in psychiatric disorders. DATA SOURCES: Bibliographic reference searches for gabapentin use in psychiatric disorders were performed in PubMed and Ovid MEDLINE search engines with no language restrictions from January 1, 1983, to October 1, 2014, excluding nonhuman studies. For psychiatric references, the keywords bipolar, depression, anxiety, mood, posttraumatic stress disorder (posttraumatic stress disorder and PTSD), obsessive-compulsive disorder (obsessive-compulsive disorder and OCD), alcohol (abuse, dependence, withdraw), drug (abuse, dependence, withdraw), opioid (abuse, dependence, withdraw), cocaine (abuse, dependence, withdraw), and amphetamine (abuse, dependence, withdraw) were crossed with gabapentin OR neurontin. STUDY SELECTION AND DATA EXTRACTION: The resulting 988 abstracts were read by 2 reviewers; references were excluded if gabapentin was not a study compound or psychiatric symptoms were not studied. The resulting references were subsequently read, reviewed, and analyzed; 219 pertinent to gabapentin use in psychiatric disorders were retained. Only 34 clinical trials investigating psychiatric disorders contained quality of evidence level II-2 or higher. RESULTS: Gabapentin may have benefit for some anxiety disorders, although there are no studies for generalized anxiety disorder. Gabapentin has less likely benefit adjunctively for bipolar disorder. Gabapentin has clearer efficacy for alcohol craving and withdrawal symptoms and may have a role in adjunctive treatment of opioid dependence. There is no clear evidence for gabapentin therapy in depression, PTSD prevention, OCD, or other types of substance abuse. Limitations of available data include variation in dosing between studies, gabapentin as monotherapy or adjunctive treatment, and differing primary outcomes between trials. CONCLUSIONS: Further research is required to better clarify the benefit of gabapentin in psychiatric disorders.

Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir.

This study investigated fexofenadine (FXD) transport and the inhibition of FXD transport in Caco-2 cell monolayer transwells, using rhodamine 123 (RH123) transport as a positive control. FXD transport from the basolateral (B) to apical (A) compartment was fivefold higher than A to B transport. FXD transport was linear with respect to time (up to 270 min) and concentration (up to 300 microm). Similar results were seen with the positive control RH123. Ritonavir (100 PM) and verapamil (100 microm) reduced transport of FXD and RH123 by more than 80%, whereas transport was not inhibited by 100 m indomethacin or 2 mM probenecid. This suggests predominantly P-glycoprotein (P-gp)-mediated transport as opposed to transport by multidrug resistance protein. In concentration-response experiments, FXD transport was inhibited by verapamil and ritonavir with IC50 values of 6.5 microm and 5.4 microm, respectively. Results from this in vitro study demonstrate differential transport of FXD across Caco-2 cell monolayers and inhibition of FXD transport by established P-gp inhibitors. Thefindings support the use of FXD as an index or probe compound to reflect P-gp activity in vivo.

Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain.

BACKGROUND: Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of neuropathic pain. In recent years, GBP has been used as an adjunct or primary therapy in non-neuropathic pain, most commonly for the treatment of perioperative and cancer pain. OBJECTIVES: The aim of this study was to conduct a clinical evidence literature review of GBP's use in perioperative pain and cancer pain. METHODS: Using PUBMED and OVID Medline databases, keyword searches for surgery and cancer in reference to GBP and pain were carried out. Nonblinded studies and case reports that did not present a unique finding were excluded. Studies that focused only on neuropathic pain were also excluded. RESULTS: An initial 142 references focusing on GBP's use in surgical pain and cancer pain were identified. Of these, 48 studies were quality of evidence at a level of II-2 or higher. DISCUSSION: Although efficacy varies, multiple well-designed clinical trials have demonstrated reduced pain and analgesic use with otolaryngology, orthopedic, mastectomy, and abdominal/pelvic surgical perioperative use of GBP, whereas there is limited or no efficacy for cardiothoracic surgery. Cancer pain studies have had greater design variability, often nonblinded, with pain benefit being mild to moderate, and more efficacious with partial neuropathic pain quality. Overall, GBP seems to have significant benefit in neuropathic and non-neuropathic pain associated with the perioperative period and cancer. Considering its favorable side effect profile, GBP represents a beneficial pain adjunctive therapy, beyond neuropathic symptoms.