Scrubbing Arteries for Stroke

Motivation: I made many resolutions this new year – one of them was to restart this blog. Many competing interests made me delinquent, but I am resolved to continue learning! For the first article of this year, we will turn to a long-standing issue in stroke neurology. Does intra-arterial therapy for stroke improve outcomes? Two years ago, I had thought about interventional neurology as a career but was dissuaded by the negative trials. Is intravenous tPA going away in 2015?

Paper: Berkhemer OA, Fransen PSS, Beumer D, et al. "A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke." NEJM (2015); 372(1): 11-20.

Methods: A randomized, multi-center, open label but endpoint blinded trial in Netherlands in which adults admitted within 6 hours of stroke onset with imaging evidence of anterior arterial circulation occlusion were randomized to usual care (including IV tPA) or usual care plus intraarterial therapy (which consisted of mechanical thrombectomy and/or intraarterial thrombolysis). The primary outcome was modified Rankin scale at 90 days (0-6 with 2 or less indicating functional independence).

Results:
Cohort: 500 subjects (233 in intervention arm and 267 in control group) were randomized with mean age of 65 years (range 23 to 96) and 58% males. Median NIH stroke scale was 17 in intervention group and 18 in control. Around 80% in both groups had prestroke modified Rankin scale of 0. IV tPA was used in 87% and 91% of subjects in intervention and control group respectively. Most common imaging finding was M1 segment MCA artery occlusion. Median time from stroke onset to randomization was 204 and 196 minutes respectively in intervention and control groups. In the intervention group, time from stroke onset to groin puncture was 260 minutes.

Clinical Outcome: At 90 days, the median mRS was 3 in intervention group and 4 in control (unadjusted odds ratio of 1.66, 95% CI of 1.21-2.28). Adjusting for variables such as time from stroke to randomization, diabetes, atrial fibrillation, etc., the adjusted odds ration is 1.67 (95% CI: 1.21-2.30). When examining for independence (mRS of 0-2), 32.6% in intervention arm vs 19.1% in control group had mRS of 0-2 at 90 days (OR of 2.16, 95% CI 1.39 to 3.38).

Radiological Outcome: No intracranial occlusion was present in 75.4% in intervention group and 32.9% in control group. Final infarct volume was 49 mL in intervention group and 79 mL in control group.

Adverse Effects: No overall difference in serious adverse effects. However, embolization into new territory occurred in 8.6% of interventions, new dissection from manipulation in 1.7%, and vessel perforation in 0.9%.

Discussion:The trial shows that addition of intraarterial therapy to conventional IV tPA may have clinical benefit. This trial is in contrast to prior ones which did not show a benefit. Two reasons (among many) are that for part of the trial, the procedure was only offered within the context of the trial resulting in inclusion of many patients. In the US, many who are likely to benefit get the procedure anyway and are not included. Secondly, all the patients in this trial unlike previous ones had known arterial occlusion by imaging prior to randomization. While the results are encouraging, this new trial could also be the one lucky one showing benefit among many failed trials. Another major deficit was that the patients were not blinded and may have been biased while reporting! We will likely need follow-up corroborative trials elsewhere prior to accepting this therapy.

Opening Pressure in Children

Motivation: I thought that the magic number for lumbar puncture was 20 cm H2O - the upper limit of normal for opening pressure. I was recently measuring the opening pressure in a 10 year old with headache, and I wondered if the opening pressure limit is the same in children. After all, the space for the cerebrospinal fluid (CSF) space is differently shaped as well as the volume of the CSF present. Turns out amazingly that this issue was addressed only in 2010 in a New England Journal publication.

Paper:  Avery, RA, Shah, SS, Licht, DJ, et al. Reference Range for Cerebrospinal Fluid Opening Pressure in Children. NEJM (2010) 363: 891-893.

Methods: A 2 year prospective study of CSF opening pressure in children between ages 1 to 18 without signs or symptoms of raised intracranial pressure or diseases which might change the opening pressure such as meningitis. The study was conducted at Children's Hospital of Philadelphia.

Results: In total, 197 children met inclusion criteria. The 90th percentile for opening pressure was 28 cm H2O while the 10th percentile was 11.5 cm H2O. Age was not correlated with increased opening pressure. Variables correlating with increased pressure included moderate to deep sedation (p = 0.002) and higher BMI (weak correlation, coefficient = 0.313). For children who were not sedated, the 90th percentile for opening pressure was 25 cm H2O.

Discussion: Compared to adults, the opening pressure for children is likely higher, and when interpreting lumbar puncture results, mildly elevated opening pressure of 25 cm H2O should not be called abnormal. There are a few questions raised by these findings though. Why is the opening pressure in general higher for children? Is it from decreased circulation space or increased relative volume of CSF? Also, I do not understand why sedation, which in general is a relaxant, should increase the opening pressure rather than decrease it. Answers to these questions may be important in management of increased intracranial pressure in children.

The Sweet Intolerance

Motivation: The last few months have been a haze - the typical residency experience. Apologies for the sparse posts. We will begin again with a relatively shocking news topic. The reputation of artificial sweeteners is under attack with allegations that glucose tolerance levels may worsen with these artificial sweeteners. Is this true or craze?

Paper: Suez, J, Korem, T, Zeevi, D, et. al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature (2014) epub.

Methods: This study consisted of two parts. The first part was in mice divided into cohorts fed water mixed with saccharin, sucralose, aspartame, or glucose/sucrose.  The metabolic profile was then determined of these mice. The second part consisted of observational human data and a small trial of saccharin in control human adults.

Results:
Non-Caloric Sweeteners in Mice: After 11 weeks of mice being fed saccharin, sucralose, aspartame, or glucose/sucrose, all three artifical sweetener cohorts had significantly worse glucose tolerance with saccharin being the worst offender. Note that these doses of sweeteners where under the FDA approved dose limit by weight. The authors replicated this finding for saccharin in two other mice cohorts randomized to either glucose or saccharin.

The author's next postulated that this effect is mediated by the gut bacteria. Treatment with ciprofloxacin and metronidazole or vancomycin abolished the glucose intolerance effect of artificial sweeteners. Furthermore, fecal transplant from mice consuming saccharin also induced glucose intolerance in the transplanted mice. The authors further postulate that short chain fatty acid production is increased in the gut with artificial sweeteners and may be part of the causal chain to increased glucose resistance.

Non-Caloric Sweeteners in Human Beings: 381 non-diabetic adults (mean age 43.3) were studied next in a cross-sectional manner. Increased consumption of non-caloric sweeteners was associated with increased weight, higher fasting blood glucose, elevated glycosylated hemoglobin, and impaired glucose tolerance test.  These associations held true independent of adjustment for body mass index.

A small trial was conducted next in seven adults who do not consume artificial sweeteners. For six days, they were fed daily saccharin up to 5 mg/kg (FDA maximum limit). After this six-day experiment, 4 out of 7 subjects developed impaired glucose tolerance. Transplant of the feces from the subjects with impaired glucose tolerance into mice elicited impaired glucose tolerance in the mice suggesting that a change in the gut microbiome may be causal.

Discussion: This paper strongly shows that use of artificial sweeteners (particularly saccharin) is associated with impairment in glucose tolerance.  Although this relationship is shown most conclusively in mice, the small trial also suggests a similar process occurring in adult human beings. Furthermore the elegant fecal transplant experiments suggest that alterations in gut flora are probably to blame. This study raises serious concerns about the artificial sweeteners. However, prior to discarding the artifical sweeteners, we need larger scale observational human studies verifying that the imbalance in glucose tolerance seen within the short duration of the trial does in fact translate to increased risk of long-term glucose intolerance and development of diabetes. Moreover, these studies again highlight the fact that when these sweeteners were approved by the FDA, no clinical endpoints were used!

Renal Denervation for Hypertension

Motivation: Yes, the blog is not dead.  It has been moribund for a while under pressure from residency. Apologies.

A previous blog post here on July 2012 had considered kidney denervation for treatment of hypertension. Recently, there was a larger trial of this technique (SYMPLICITY HTN-3) was reported. So, should be all be considering this treatment for refractory hypertension?

Paper: Bhatt, D.L., Kandzari, D.E., O'Neill, W.W. et. al. "A Controlled Trial of Renal Denervation for Resistant Hypertension." NEJM (2014); 370: 1393-401

Method: Prospective blinded randomized sham-controlled trial in adult patients with severe resistant hypertension. Subjects were randomized in 2:1 ratio to undergo renal denervation or a sham procedure. Severe resistant hypertension was defined as three drugs at maximum doses. Primary endpoint was change in systolic blood pressure at six months.Of note, patients with renal artery stenosis were excluded.

Results:
Cohort: Total of 535 patients were randomized in this trial (364 to renal denervation group and 171 to sham procedure). The average age was about 57 years with roughly 60% of male patients. Baseline characteristics including body mass index, race, kidney disease, cardiovascular disease, and rate of smoking were not different between the two groups. On average, subjects took five antihypertensive medications.

Primary outcome: At six months, the intervention group had 14.13 mmHg decrease in SBP compared to 11.74 mmHg decrease in the sham group. This difference was not statistically significant.

Safety: There were five adverse effects in the intervention group compared to one in the sham group. There was no difference kidney function in the intervention group.

Discussion: This trial shows that renal denervation is not worth pursuing in the severely refractory hypertensive group of patients. The question remains why the therapy appeared so promising in the smaller trial but failed now.  One possible reason is that in the smaller previous trial, the placebo and the intervention groups were not well matched while the two groups are well matched in this trial. While this trial did not have promising results, one wonders whether this same procedure might benefit patients with early hypertension who may still respond to renal denervation. However, for now, I would not recommend this therapy.

Radiation Dementia Treatment

Motivation: Dementia is a dreadful word - a terminal cognitive decline ending in dependence and ultimately death.  Among the many causes, prior history of whole brain radiation is a risk factor.  Recently, a friend in radiation oncology told me that there was a trial for this kind of dementia with memantine.  How good is it?

Paper: Brown, PD, Pugh, S, Laack, NN et. al. "Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial." Neuro-Oncol (2013); 15 (10): 1429-37.

Method: Eligible patients were adults with metastatic solid cancer to the brain receiving whole brain radiation with good performance status without renal failure and mini-mental status exam score > 18.  Patients were randomized to placebo or memantine (titrated up to 10 mg twice daily for length of 24 weeks).  Primary end-point was cognitive function (as measured by Hopkins Verbal Learning Test-Revised) at 24 weeks.

Results:
Cohort: Total of 508 patients randomized with 56% female.  Most common malignancy is lung cancer (70%).  256 were randomized to memantine while 252 were randomized to placebo. There were no differences in baseline age, gender, neurological functional status, education, prior history of radiation, or baseline neurocognitive score.

Compliance: Study compliance for the drug was 31% for memantine arm and 33% for placebo arm.  The most common reasons for discontinuation were patient refusal and patient death followed by disease progression or adverse event (similar in both groups).

Outcome: Compared to the placebo group, there was decreased decline in Hopkins Verbal Learning Test-Revised scale (0 for memantine vs. -0.9 for placebo, p = 0.059).  There was a statistical benefit in terms of Mini Mental Status Exam (0 vs -1, p = 0.0093).  There were no differences in progression-free survival or overall survival.

Adverse Effect: No statistical difference in adverse effect between groups.

Discussion: This trial seeks to hint that memantine may have some cognitive benefit in whole brain radiation, but the trial is seriously hampered by the very poor study compliance (2/3 or more of the patients did not comply with study assignment).  Also, the statistically significant Mini-Mental Status Exam improvement by one point is likely not clinically meaningful.  At present, I would say that the efficacy of memantine remains unanswered awaiting further testing.

Pain in Sjogren's Syndrome

Motivation: Every time someone comes with painful feet, I ask "Do you have dry mouth or dry eyes?" Patients usually look at me suspiciously.  What does dry eyes have to do with painful feet?  Sjogren's syndrome, of course  - an elusive syndrome of dry eyes, dry mouth, and autoimmune destruction of exocrine glands often with associated peripheral neuropathy.  To avoid those suspicious glances, I wonder what are the characteristics of neuropathy from Sjogren's syndrome.

Paper: Berkowitz, AL and Samuels MA. "The neurology of Sjogren's syndrome and the rheumatology of peripheral neuropathy and myelitis." Pract Neurol (2013); 0: 1-9.

Methods: Review of peripheral nervous system presentations of Sjogren's syndrome and characteristics of serologic testing.  This is part of a broader paper reviewing Sjogren's associated myelitis as well.

Results:
Prevalence: Neuropathy accompanies Sjogren's syndrome in approximately 5-15% of cases.  Neuropathy preceded other symptoms in 37%, occurred concurrently in 16%,and occurred after other symptoms in 37%.

Types of Neuropathy: The most common forms of neuropathy involve the dorsal root ganglia (hence pure sensory loss) in 39% and small unmyelinated fibers (hence painful) in 20%.  Other presentations included trigeminal neuropathy in 16%, multiple mononeuropathies in 12%, multiple cranial neuropathies in 5%, and polyradiculoneuropathies in 4%.

Testing: The classical serum auto-antibodies anti-Ro (SSA) and/or anti-La (SSB) occur in 10-55% of patients with Sjogren's neuropathy.  For dorsal root involvement, the sensitivities of SSA and SSB are 53% and 11%.  For painful small fiber neuropathy, the sensitivities of SSA and SSB are 39% and 17%.  Anti-nuclear antibody (ANA) is positive in 20-67%.  Schirmer's test evaluating tear production (degree of moistening of filter paper in lower eyelid after 5 minutes) is positive in 56-89%.  Lip salivary gland showing lymphocytic infiltration is diagnostic in 37-75% of patients.

Discussion: 
The first depressing conclusion of this paper is that the manifestations of Sjogren's syndrome are protean without good diagnostic tests.  Nonetheless, Sjogren's associated neuropathy is most often sensory in nature (dorsal root gagnlia or just painful neuropathy) without significant motor involvement.  The second point is that serologic testing may be negative in about 50% or even more number of patients.  Similarly, classical symptoms of dry eyes or dry mouth may follow neuropathy and should not be used to exclude Sjogren's syndrome.  In the office, stocking filter paper and learning to perform the Schirmer's test may be more helpful than sending for serologic testing.  

Lipoprotein (a) Value

Motivation: Lipoprotein (a) inspires strong emotions among doctors.  Some like it as a risk factor while others see it as a waste of money.  But, when controlled for conventional lipid markers, is it indicative for additional risk for cardiovascular disease?  For background, lipoprotein (a) is a low density LDL-like particle synthesized by the liver which is found in the intima of arteries and presumably promotes atherosclerosis.

Paper: The Emerging Risk Factors Collaboration. "Lipoprotein (a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality."   JAMA (2009); 302: 412-423.

Methods: Meta-analysis of long-term prospective studies that recorded Lipoprotein (a) (Lp(a)) and vascular morbidity.

Results:
Studies: 36 prospective studies met inclusion criteria.  In the analysis, 126 634 participants were included for 1.3 million person-year of follow-up with 22 076 vascular disease outcomes or death.  Mean age at entry was 57 years with 48% women.  Ethnicity was 47% European and 50% North American.

Lipoprotein (a): At baseline, the overall population Lp (a) was 12.6 mg/dL.  Blacks had 119% (95% CI: 84 to 161) higher Lp(a) concentration compared to whites at baseline.  Women had 12% (CI: 8 to 16) higher Lp (a) than men.

Coronary Heart Disease (CHD): When adjusted for age, sex, systolic blood pressure, smoking, diabetes, and total cholesterol, the relative risk of coronary heart disease for the top third of Lp (a) compared to the bottom third was 1.27 (95% CI: 1.17-1.38).  In the top third of subjects with Lp (a), the rate of CHD was 5.6 (95% CI: 5.4-5.9) per 1000 person years compared to rate of 4.4 (95% CI: 4.2-4.6) per 1000 person years in the bottom third.

Ischemic Stroke: When adjusted for usual risk factors, the relative risk (RR) for ischemic stroke was 1.10 (95% CI: 1.02-1.18) per 3.5 fold higher than usual Lp (a) levels.  The relative risk did not reach significance for unclassified stroke and hemorrhagic stroke.

Non-vascular mortality: Lp (a) levels were not associated with increase in non-vascular mortality.

Discussion: Lipoprotein (a) is very modestly associated with independent risk of coronary heart disease and ischemic stroke.  As stated in the paper, compared to the power of Lp (a), elevated non-HDL cholesterol level is four times more strongly associated with coronary heart disease.  There is no drug that independently targets Lp (a) levels.  Consequently, I do not think that at present, it is worth measuring this modestly predictive marker without clear treatment.  The paper, though, illuminated the variability of Lp (a) across ethnicities (blacks have baseline of 100% greater than whites) and genders.  When interpreting raw values of Lp (a), we have to be careful about using correct gender and ethnicity matched norms, which may not exist in all cases.