Tuesday, March 18, 2014

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.

Sunday, February 16, 2014

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 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.  

Tuesday, February 4, 2014

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.

Monday, January 27, 2014

Cooling Dogs

Motivation: Lately, hypothermia has not been good enough for me.  There have been too many people who have suffered cardiac arrests at home and ended up severely impaired despite receiving mild hypothermia according to protocol.  Can we do better?  For instance, if we can quickly institute deep hypothermia, is it any better?

Some of the coldest studies in this field have been performed in dogs.  In this amazing study, dogs were tested for neurological recovery after many hours of hypothermia.

Paper: Nozari A, Safar P, Wu X, et. al. "Suspended Animation Can Allow Survival without Brain Damage after Traumatic Exsanguination Cardiac Arrest of 60 Minutes in Dogs." J Trauma (2004); 57: 1266-1275.

Methods: Fourteen dogs were sedated with ketamine and halothane and supported with positive pressure ventilation.  The dogs were then exsanguinated over fiver minutes to cardiac arrest.  At two minutes, flush of saline at 2 degrees Celsius was administered in femoral artery to achieve tympanic temperature of 10 degrees Celsius.  In 6 dogs, reperfusion was performed after 60 minutes of cardiac arrest.  In 8 dogs, to simulate trauma, splenic injury was inflicted prior to cardiac arrest.  During arrest time of 60 minutes, the spleen was transected.  Outcome was determined by overall performance category (1 to 6 with 1 being normal and 6 being death) at 72 hours.

Results:
Resuscitation: All fourteen dogs were successfully resuscitated from cardiac arrest.

Control group: All six dogs in the control group were neurologically normal after 72 hours (they were judged to be identical in behavior to their pre-intervention condition).

Trauma group: Of the eight dogs who underwent splenectomy during the cardiac arrest time, four were normal after resuscitation.  One had moderate disability while another dog had severe disability.  Two dogs remained in coma.

Discussion: In this remarkable study, dogs could be maintained in suspended animation at 10 degrees Celsius when rapidly cooled after two minutes.  The most obvious problem in extending this strategy to the real world is that Emergency Medical response time is certainly greater than two minutes.  However, while we know that delayed cooling leads to increased brain injury, trials using suspended animation have not been tried in human beings even in settings in which prompt response is possible (such as hypothermia instituted in the field).  One of the other interesting findings in the study is that operative trauma during suspended animation (splenectomy) leads to a worse outcome after reperfusion.  The cause is unclear in this case but could be secondary to need for increased recovery times (all dogs were timed at 72 hours and not at best long term performance) or possibly injury from increased systemic inflammation.

Thursday, January 2, 2014

Proton pump inhibitors in liver cirrhosis

Motivation: A patient with known liver cirrhosis is admitted. His home medication list includes a proton pump inhibitor (PPI). If there is no other indication (such as peptic ulcer disease), what is the evidence for use of PPIs in liver cirrhosis - in particular, are PPIs effective in preventing GI bleed in liver cirrhosis? Are there any risks associated with PPI use?

Literature:
1) LEVEL OF EVIDENCE: retrospective study
 Garcia-Saenz-de-Sicilia M et al. PPIs are not associated with a lower incidence of portal-hypertension-related bleeding in cirrhosis. World J Gastroenterol. 2010 16(46):5869-73.

This was a restrospective study that included 105 patients with cirrhosis with endoscopy-proven portal hypertension. Patients were divided into 2 groups: those who used PPIs (45.5%) and those who did not. Seventeen (16.1%) patients had upper GI bleeding, due to either esophageal varices or portal HTN gastropathy. Of these 17 patients 9 used PPIs, while 8 did not use PPIs (p=0.51). Thus, in this retrospective study, use of PPIs was not associated with development of GI bleed related to portal HTN.

2) LEVEL OF EVIDENCE: literature review
Siple JF et al. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. 2012 46(10):1413-8.
This was a literature review that evaluated the use of PPIs in cirrhosis and ascites, ultimately including 1 case study, 8 restrospective case-controlled studies, 1 meta-analysis. Authors summarize that there is a possible risk of association between use of PPIs and increased risk of SBP and C diff infection in cirrhosis/ascites. However, they note that this association has yet to be established by prospective trials.

3) LEVEL OF EVIDENCE: RCT 
Shaheen NJ et al. Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005; 41(3):588-94
In this study, the use of PPI after elective esophageal variceal ligation (EVL) was investigated. This study was designed as a double-blinded, placebo-controlled RCT where 44 subjects (42 completed the study) who underwent EVL were randomized to the pantoprazole arm (pantoprazole 40 mg IV after EVL x 1 then pantoprazole 40 mg PO x 9 days) or the placebo arm (placebo IV x1 after EVL then placbo PO x 9 days). Upper GI scope 10-14 days after the EVL procedure showed that while both groups had the same mean number of ulcers, ulcers in the pantoprazole arm had smaller average size (p < 0.01). 
Thoughts: I was unable in my initial literature search here to find definitive evidence that PPIs should be used for primary prevention for GI bleeding secondary to portal hypertension in liver cirrhosis. One retrospective study by Garcia-Saenz-de-Sicilia et al. (2010) did not show differences between patients who took PPIs and those who did not, but this was a relatively small sample that was studied retropectively. The RCT by Shaheen et al. (2005) provide evidence for using pantoprazole directly after EVL, though it was a short, limited course of PPI use that was studied. Authors Siple et al. (2012) recently draw from existing literature to caution on the potential risk of infection (SBP, C diff) when using PPIs, though there is no prospective, RCT evidence for this concern. It is important to think about the indications of using PPIs in patients, realizing that there lacks evidence for use of PPIs in primary prevention of GI bleeds related to portal HTN in liver cirrhosis (Garcia Saenz-de-Sicilia et al., 2010). While one should be aware of possible adverse effects like increased risk of infection (Siple et al., 2012), there also does not exist evidence against using PPIs in liver cirrhosis if there is a reasonable primary indication for PPI use (e.g. peptic ulcer disease).

Thursday, December 26, 2013

Blood Pressure Goals

Motivation: 150?? Since medical school, we have been firmly taught that the upper limit of normal for systolic blood pressure is 140 mmHg.  Recently, the panel JNC8 ruled that for adults over 60, a reasonable systolic goal is less than 150 mmHg.  After having counseled countless times about the importance of blood pressure control, this increase sounded traitorous.  What is the data?  There have been two randomized trials addressing this issue over the past decade.  I will review here the one of the larger and latest one here.

Paper: Ogihara, T, Saruta, T, Raguki, H, et. al.  "Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly" Hypertension (2010) 56: 196-202.

Methods: The study (VALISH) was a multicenter, prospective, randomized, open-label, blinded end point trial in Japanese adults between 70-85 years of age with isolated systolic hypertension (SBP > 160 mmHg with diastolic less than 90 mmHg).  Patients were randomly treated with valsartan (titrated first with addition of second agent if necessary) into two groups: (1) Systolic blood pressure < 140 mmHg (strict control) or (2) systolic blood pressure < 150 mm Hg (moderate control).  Patients were followed for minimum of two years.  Primary outcome was a composite of cardiovascular events (sudden death, stroke, MI,  death from cardiovascular cause, renal dysfunction).

Results:
Cohort: A total of 3260 patients were randomized.  There were 181 patients lost to follow-up (95% follow-up).  In total, 3079 patients were followed for average of 2.85 years.  Average age was 76.1 years with 62% women.  Baseline characteristics were mostly balanced between groups except there were more smokers in the strict control group vs. moderate control (21% vs. 17.4%; p = 0.01).  There was history of stroke in 6.5%, ischemic heart disease in 5%, heart failure in 1.7%, and diabetes mellitus in 13%.

Blood Pressure Control: At 36 months of follow-up, the blood pressure was 13.6./74.8 in strict control group and 142/76.5 in moderate control groups.  Heart rate did not differ significantly between the two groups.

Outcome: In the primary combined cardiovascular outcome, the overall rate did not differ between the groups in intention-to-treat analysis (10.6 events per 1000 patient years in strict control; 12 per 1000 patient years in moderate control group, p = 0.38).  There was no difference in any of the individual components of the composite outcome.  In subgroup analysis, there was not a statistical difference in patients with diabetes, dyslipidemia, and chronic kidney disease.

Adverse Effect: There was no difference in adverse effect between the two groups.

Discussion: After an average of 2.8 years of follow-up, there did not appear to be a difference in cardiovascular outcome by controlling blood pressure tighter in patients with isolated systolic hypertension.  While rather remarkable and against popular medical conception, I think that the lack of longitudinal data beyond 2.8 years is cautionary is depending on these blood pressure parameters too much.  This trial shows that systolic blood pressure control less than 150 mmHg versus 140 mm Hg may not make much of a difference in the short term, but what about in five to ten years?  We still do not know the answer.  Another problem with extending this dataset is that patients included in the cohort had low burden of disease (ischemic heart disease in only 5%).  For the patient with angina, the trial may not be powered enough to detect difference in this subgroup.    But then again, these arguments are probably my ingrained cognitive biases against change.  The bottom line, I think, is that we need more longitudinal data before having a blood pressure parameter in mid.

Monday, December 9, 2013

Stroke Recovery for How Long

Motivation: So, how long does it take to recover? Even after more than a year of treating patients with acute stroke, I am not sure how to answer this question.  I sometimes put it vaguely as "months."  But, really, after how many months do most post-stroke patients complete their recovery?

Paper: Jorgensen HS, Nakayama H, Raaschou HO, Vive-Larsen J, Stoier M, Olsen TS. "Outcome and time course of recovery in stroke: Part II: Time course of recovery. The copenhagen stroke study." Arch Phys Med Rehabil (1995); 76: 406-412.

Methods: All patients with acute stroke in Copenhagen, Denmark between September, 1991 to 1993 were followed from time of acute admission to end of rehabilitation to six months post-stroke.  Time course of recovery was plotted.

Results:
Cohort: The cohort of stroke survivors consisted of 947 patients (53% female) of mean age 73.3.  The strokes were 93% ischemic and 7% hemorrhagic.  The median time between symptom onset and admission was 16 hours.  After rehabilitation, 19% were placed in nursing homes while 81% were discharged home.

Recovery: When assessed by the Scandinavian Stroke Scale (0-58 points, higher indicating milder deficits), best neurological recovery was reached in 80% by 4.5 weeks (95% CI: 4 to 5 weeks) and in 95% by 11 weeks (95% CI: 10.1 to 11.9 weeks) from stroke onset.  Best ADL function (measured by Barthel Index) was reached in 80% by 6 weeks (95% CI: 5.3 to 6.7 weeks) and in 95% by 12.5 weeks (95% CI: 11.6 to 13.4).

Initial Severe Functional Deficits: Severity of functional deficits were judged by the Barthel Index (scale of 0 to 100 with very severe disability in 0-20 and no disability with score of 100).  In those with very severe initial disability (index of 0-20), best ADL function was reached in 80% of patients within 11 weeks (95% CI: 10-12) and in 95% within 17 weeks (95% CI: 15-19).

Initially Mild Disability: In those with mild disability (Barthel Index 75-95), best ADL function was reached in 80% of patients within 2.5 weeks (95% CI: 2-3) in 95% of patients within 5 weeks (95% CI: 4-6).  

Discussion: In this remarkable study with 100% follow-up of all stroke patients in Copenhagen over two years, the overall message is that 95% will regain their best ADL function in about three months.  The rate of recovery is slower in those with more severe disability and more rapid in those with mild disability.  However, even in those with very severe initial functional deficits, best ADL function was reached in 17 months.  For general counseling purposes, an appropriate summary statement might be that mild strokes take about a month to regain best function while severe strokes take about four to five months to regain best function.  While this study is well done, some cautionary aspects are that (1) acute stroke therapy has changed since  the study, and (2) physical therapy has changed since the early 1990s.  How these aspects change the natural history of stroke disorders is unclear.  Also note that this study also talks about the rate of recovery and not the extent of recovery.