Causes of Flapping

Motivation: Look - the hands are flapping.  One of the useful tests in a confused patients is to ask them to stop traffic with outstretched hands.  If the hands start flapping in a non-rhythmic way ('asterixis'), that is interpreted as proof of generalized toxic-metabolic encephalopathy.  But, then again, there is probably a neural pathway underlying this mechanism.  We often dismiss asterixis in a blase way, but can there be focal brain lesions underlying asterixis?

Paper: Degos, J-D., Verroust, J., Bouchareine, A., et. al. "Asterixis in Focal Brain Lesions"  Arch Neurol. (1979); 36: 705-707

Methods: At Henri Mondor Hospital (Creteil, France), one of the authors documented twenty cases of asterixis with focal brain lesions.  EMG was available for nine patients.

Results:
Midbrain Lesions: Four patients ranging from 38 to 62 years presenting with unilateral asterixis after abrupt onset weakness in the affected side.

Parietal Lesions: Seven cases of asterixis with pathologic proof in four occurred from parietal lesions.  These lesions could occurred on contralateral side from the asterixis and could be from mass lesions (glioblastoma, abscess, metastatic lesion) or from stroke (hemorrhagic or ischemic).

Suspected Midbrain and Parietal Lesions: Six cases with suspected lesions.  One of these cases was a right temporal glioblastoma invading the lenticular nuclei with left sided asterixis and another had an expanding right thalamic tumor with left sided asterixis.

Unclear lesions: Three cases of unilateral asterixis with accompanying unilateral weakness or numbness of unclear etiology.

EMG Recordings: During episodes of asterixis, there were 50-100 ms periods of electrical silence in both agonist and antagonist.

Discussion: This old paper shows that true asterixis is not purely a toxic-metabolic phenomenon.  Apparently, parietal, midbrain, and thalamic lesions can result in contralateral asterixis.  While this paper certainly does not suggest a pathophysiological explanation of asterixis, some important points are that: (1) asterixis appeared contralateral to the lesion meaning that usually the side with asterixis is the one that is weak or numb, (2) both cortical and deep lesions can result in asterixis,.  I think that this account provides a cautionary note of dismissing asterixis as purely toxic phenomenon.

Interfering with RNA

Motivation: In medical school, while watching cartoons depicting disease pathophysiology pathways, I have thought many times that if we could just somehow block that damaged protein, we will cure that disease.  In mice, of course, multiple techniques exist including creating mutant breeds, transfecting with viruses, or injecting short RNA interfering sequences.  I was thrilled to read last month that such magic has for the first time been tried successfully in human beings.  Given the momentous significance of the recent trial testing RNA interference in transthyretin amyloidosis, we will cover the technique and consequences.

Paper: Coelho, T., Adams, D., Silva, A., et. al. "Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis" NEJM (2013); 369: 819-29.

Methods: This Phase I study consisted of two parts.  In the first portion, eligible patients were older than 18 years with biopsy proven transthyretin amyloidosis with mild-to-moderate neuropathy.  Patients were excluded if they had liver, renal, or thyroid dysfunction.  These patients were injected in a blinded way with lipid nanoparticles containing RNA interfering (RNAi) sequences or with placebo.  In the second part, seventeen healthy patients were injected with a second generation lipid nanoparticle containing RNAi sequences testing for safety.

The lipid nanoparticles consisted of ionizable lipid components with RNA sequence that targets a conserved sequence at the 3' untranslated region of mRNA of Transthyretin protein (TTR).

Results:
Cohort: In the cohort with disease, there were 32 patients with 56% male and median age of 37.  Majority of participants were recruited from Portugal (23/32 patients).  The healthy volunteer cohort were all 17 male subjects with mean age of 27 (all were from England).

Amyloidosis Cohort: Patients with TTR amyloidosis treated with placebo did not have change in serum transthyretin levels.  In the group receiving 1mg/kg lipid nanoparticle dose, there was a mean reduction of 38% in serum transthyretin levels with recovery to close to baseline levels by day 28.

Healthy Volunteers: Using the second generation lipid nanoparticles, peak reduction of serum transthyretin level was reached at approximately day 10.  At 0.3 mg/kg and 0.5 mg/kg doses, the mean levels of suppression were 82.3% and 86.8%.  The serum transthyretin levels remained suppressed even at day 28.

Safety: There were no drug related serious adverse events or study drug discontinuation.  No significant changes in hematologic, liver, or renal measurements were seen.  Mild to moderate infusion reactions occurred in 7 to 20% of reactions responding to temporary interruption of infusion or administration of glucocorticosteroids.  Antibodies to pegylated lipid components were not seen.

Discussion: This trial demonstrated successful use of lipid nanoparticle RNAi to suppress transthyretin levels.   In the four week follow-up, there were remarkably no drug related side effects.  This Phase I trial, while promising, does not show efficacy of treatment on important clinical variables.  Transthyretin is primarily synthesized by the liver but is also synthesized to a smaller extent in the retina and choroid plexus.  The hepatic suppression may still leave the patient vulnerable to retinal and CNS side-effects.  In normal physiology, transthyretin is associated with retinol binding protein levels and Vitamin A levels.  Long term suppression of transthyretin may also interfere with Vitamin A metabolism.  Also, it is unclear whether repeated administration of lipid nanoparticles will generate an immunologic response.  Nonetheless, the trial is an encouraging start on selective suppression of hepatic protein synthesis.

Propofol and sepsis

Motivation: Sepsis is one of the most common issues in the ICU, and for any number of reasons, patients with sepsis also could require intubation and sedation. Practically speaking, propofol and midazolam are both commonly used in the ICU for septic patients who require sedation, weighing their risks and benefits in the individual patient. There are some benefits of propofol over midazolam in critical care patients in general (1), so I wondered whether there were risks associated with using propofol in the setting of sepsis. This discussion excludes the issue of contaminated propofol preparations. I found one paper that raised clinical concerns about the association between propofol and infection/sepsis.

Study:  Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7. 

Design: Nested cohort study of patients who were enrolled in a randomized control trial on another topic (comparing different regimens of insulin therapy). Patients who were on propofol were compared to those who were not on propofol, in terms of baseline characteristics and outcomes. ICU-acquired infections were defined as those found at least 48 hours after ICU admission and up to 48 hours after discharge, while ICU-acquired sepsis was defined as per standard criteria (2).

Results: There were differences in baseline characteristics between the two groups of patients; compared to no propofol, propofol group were more likely to be mechanically ventilated but less likely to have severe illness, chronic renal disease, immunosuppression or cardiovascular disease. In adjusted statistical analysis, propofol use was associated with increased risk of ICU-acquired infection (95 CI 1.17-3.05, p=0.009), and ICU-acquired severe sepsis and septic shock (95 CI 1.12-3.28,p=0.02). There were no statistically significant differences in ICU or hospital length of stay or ICU or hospital mortality (2). 

Discussion: This study had convincing evidence as above for a relationship between propofol use and infections, and discusses potential reasons why propofol may be associated with increased risk of infectious including impairment of host immune cell function, increased lipid levels affecting mitochondrial oxygen use, growth of bacteria in propofol emulsion, increased lipid caloric intake (2); however, it is important to emphasize that these are potential reasons based on studies or observations in other contexts that are not necessarily generalizable to the septic ICU patient. In terms of study limitations, it is important to note that the study showed a statistical association (not causation) between use of propofol and increased risk of ICU-acquired infection or sepsis in a post-hoc study on a trial designed for another indication (2). Noted that this study did not compare propofol versus midazolam, nor did I find a similarly designed study for midazolam.

I was surprised to see that there were several animal studies that showed benefit of propofol (versus no propofol) in animal models of sepsis. A few examples of these studies are here; most of the sample sizes are modest. In an animal study specifically designed to study the effect of propofol on a rat model of sepsis (cecal ligation and puncture), rats treated with early or late propofol had statistically significant higher survival rates than rats without propofol treatment (3). Propofol-treated rats also had statistically significant lower levels of ALT, AST, BUN, Cr and CK (3). In the same rat model of sepsis, rats treated with propofol had improved hypotension, lower plasma levels of TNF-alpha, IL-6, and more suppression of NF-kappaB activation (4). Another study reported that midazolam had an overall anti-inflammatory effect in a macrophage cell line through various mechanisms (5).

Looking for more studies of animal models of sepsis and sedation, I found a paper on the same rat model of sepsis comparing the effects of propofol and midazolam on neutrophil function (6). In both early and late time points of sepsis, propofol and midazolam decreased hydrogen peroxide production by neutrophils with propofol associated with statistically signficantly more decreased production than midazolam (6). These results suggest at least in the in vitro context that propofol might attenuate neutrophil function in this rat model of sepsis, favoring midazolam over propofol if results could be extrapolated to clinical context (6). Also, it was very interesting to note in this study that there was negligible effect of the lipid propofol carrier on neutrophil hydrogen peroxide production (6).

Conclusion: Overall, there lacks definitive evidence comparing propofol and midazolam in ICU patients with sepsis; however, one clinical study brought up concerning associations between propofol and ICU-related infection (2), while one animal model study showed that midazolam would be better than propofol in rat models of sepsis as it interfered less with neutrophil function (6). These concerns should be taken into account when weighing the risks and benefits of midazolam versus propofol for the septic ICU patient.

References:

1.     Carrasco G, Molina R, Costa J, Soler JM, Cabré L. Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis. Chest. 1993 Feb;103(2):557-64.

2.     Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7.

3.     Bao HG, Li S. Effects of propofol on the outcomes of rats with sepsis. J Surg Res. 2011 Jun 1;168(1):e111-5. doi: 10.1016/j.jss.2010.12.034. Epub 2011 Jan 22.

4.     Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, Liang H. Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep. 2009 Nov;36(8):2345-51. doi: 10.1007/s11033-009-9456-z. Epub 2009 Feb 4.

5.     Kim SN, Son SC, Lee SM, Kim CS, Yoo DG, Lee SK, Hur GM, Park JB, Jeon BH. Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage. Anesthesiology. 2006 Jul;105(1):105-10.

6.     Inada T, Taniuchi S, Shingu K, Kobayashi Y, Fujisawa J, Nakao S. Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis. Anesth Analg. 2001 Feb;92(2):437-41.

Abdominal pain and seizures

Motivation: A man walks in to the hospital with seizures also complains of periodic stomach pain.  I wonder could it also be a seizure?  After all, migraines in children are clearly linked to episodes of abdominal pain.  Could epileptic discharges create a similar phenomenon?

Turns out that this issue has been thought of by many - in fact, Trousseau had also thought about the issue in 1868.  Reviewed here is a compilation of the common clinical presentation.

Paper: Zinkin, NT, Peppercorn, MA. "Abdominal epilepsy" Best Practice & Research Clinical Gastroenterology (2005); 19(2): 263-274.

Methods: Review of 36 reported cases in english literature.  Patients were required to have paroxysmal EEG abnormalities with correlated clinical spells.

Results:
Clinical Characteristics: In meta-analysis of 36 published cases, most frequent feature was a sharp pain (86%) commonly in peri-umbilical and upper abdominal pain.  Nausea and vomiting was an infrequent feature in 28% followed by diarrhea (5%) and bloating (3%).  Besides abdominal pain, some disturbance in consciousness was observed in 64% ranging from generalized seizures to dizziness.  Duration of seizures was at most a few minutes.  EEG did not have a consistent localization for inter-ictal epileptiform activity.

Discussion: I think that abdominal epilepsy is worth considering as a diagnosis in someone with bouts of brief abdominal pain with some change in consciousness/"funny" feeling.  There are many people - often hard to treat people - with unexplained abdominal pain.  Some get unsatisfactory diagnosis of irritable bowel syndrome or somatoform disorders.  If there is no other explanation, an EEG may be in order.

After statin-induced myopathy: What next?

Motivation: A frequent finding in both the hospital and outpatient setting is the patient with hyperlipidemia and/or coronary artery disease who was on a statin, but had to stop due to side effects, mainly muscle cramps. Some of these patients have been switched to a different statin, are on a lower dose of the same statin, or not on any statin at all. There appears to be no consensus on what comes next. This observation had me running toward the literature wondering what the data shows for best treatment option in patients who have had adverse effects (e.g. myopathies) from statin use.

Papers:
Reinhart KM and Woods AJ. Strategies to preserve the use of statins in patients with previous muscular adverse effects. Am J Health Sys Pharm 2012; 69:291-300.
Robenson, RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408-416.

Background: Statins have a number of adverse effects, the most common being myopathies (usually bilateral leg cramping) that may cause serum elevations of the muscle enzyme creatine kinase (CK). About 10% patients discontinue statins after 1 year and 28% after 4 years and nearly half of these due so because of the adverse effects. An estimated 1 out of 5 people on statins will have some adverse myopathic reaction in their lifetime. The mechanism is not entirely understood, but the most convincing hypothesis is that statins as HMG-CoA reductase inhibitors inhibit the production of mevolonate, a precursor to not only artery-clogging cholesterol but also the "good" cholesterol that supply our cellular membranes. Furthermore, mevalonate is a precursor of ubiquinone (coenzyme Q10) which is a powerful antioxidant, membrane stabilizer, and essential player in the ATP chain that leads to the production of energy that myocytes rely on to do their job.

Methods:
Unfortunately, no large-scale randomized trials have been done to address this issue. Reinhard and Woods conducted the largest literature review on an understudied field that included 16 restrospective studies, and some intereventional (not all randomized or controlled) trials that examined the outcomes of a strategy for the preventon of recurrent statin-associated myalgia.

Results:
Five options were found in the literature: 1) reduced dosing of statin 2) addition of vitamin D or E to statin therapy 3) addition of supplemental coenzyme Q10 to statin therapy 4) red yeast rice as substitution for statin (RYR contains a naturally occuring lovastatin) 5) trial of a different statin. For patients reduced from once daily to once or twice a week regimen of atorvastatin, about 20% were able to significantly lower their statins to reach goal and there was no difference compared to placebo in the incidence of myalgias suggesting that this is a more tolerable, if less effective option. Vitamin E did not show any benefit in reducing myalgias, while vitamin D added to statins showed a mild effect. CoQ added to a statin had conflicting data with some showing significant decrease in myalgias in RCT, and others showing none. RYR had difficult to interpret data mainly because it is a supplement that is not approved by FDA to contain any lovastatin in US (whereas it contained varying degrees of lovastatin in the reviewed studies). Trial of alternative statins showed fairly good results (>90% tolerability in 3 RCTs) when patients were switched from a different statin to an equivalent dose of fluvastatin (80mg), atorvastatin (10-20mg), or rosuvastatin (5-10mg).

Discussion:
Overall, using an alternative statin may be the most tolerable and efficacious option after discontinuance of a previous statin due to adverse effects. It is thought that hydrophilic (water-loving) statins are less likely to cause symptoms as they cannot cross the cell membrane easily through passive diffusion (unlike lipophilic statins). For example, simvastatin is a commonly used lipophilic statin that is known to cause adverse effects whereas rosuvastatin, a hydrophilic drug, is much less likely to do so. Vitamin D or CoQ supplementation may be helpful in patients with mild symptoms and no elevation of creatine kinase. RYR should not be used because it does not include the active ingredient (e.g. lovastatin) when purchased in the US and has previously been shown to contain nephrotoxic additives. These interpretations are very limited given that there has been no head to head studies and the few trials that exist are in relatively small samples with poor controls and ample potential for bias. As a future preventative cardiologist, I must advocate against the discontinuation of statins altogether. The data showing the ability of statins to prevent MI and death from cardiovascular causes even in patients with normal lipid levels is powerful, indeed. The biggest conclusion I can draw is that pragmatic, randomized clinical trials comparing these options are desperately needed.

Intravascular Lymphoma

Motivation: Zebras are growing more frequent these days.  Though thought to be quite rare, I have seen two of my favorite patients diagnosed with intravascular lymphoma within the past year.  In both, the diagnosis could not be made for months because of the non-traditional lymphoma findings - for instance, no enlarged lymph nodes.  Intravascular lymphoma is characterized by growth of lymphoid neoplastic cells with the lumen of blood vessels.  Given lack of systemic masses, are there clinical clues to its diagnosis?  We will review here one of the largest review of cases for this rare disorder.

Paper: Ferreri, A.J.M., Campo, E., Seymour, J.F. et. al. "Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'" Brit. J. of Haematol. (2004); 127: 173-183

Methods: Data gathered from 22 centers forming the International Extranodal Lymphoma Study Group (IELSG) on patients who were  HIV negative and were diagnosed with intravascular lymphoma between 1985 and 2003.

Results: 
Cohort: Intravascular lymphoma was diagnosed in 38 patients - postmortem in eight (21%) and while living in 30 (79%).  The median age was 70 years with male/female ratio of 0.9.

Clinical Presentation: The most common presenting symptom was fever in 45%.  Systemic symptoms including fever, weight loss, or night sweats were present in 55%.  Cutaneous lesions were present in 39% made up of a wide variety of lesions including erythematous eruption, plaques, swelling, nodular discolorations, or small red palpable spots situated in upper arms, thighs, legs, lower abdomen, or breast.  The next most common finding was neurological symptoms present in 34% with a wide range of symptoms from focal deficits to meningoradiculitis.

Laboratory Variables: The most common lab abnormality was elevated serum LDH (86%) followed by elevated beta-2 microglobulin (82%).  ESR was elevated in 43%.  Anemia was present in 63% while leukopenia and thrombocytopenia were present in 24 and 29% respectively. 

Discussion: Intravascular lmphoma remains a difficult disorder to diagnose.  I think that patients with unclear lesions in the brain and skin with systemic symptoms should raise suspicion of intravascular lymphoma.  The present large series also contrasts with previous reports from Japan where intravascular lymphoma presented more commonly with hemophagocytic syndrome and less commonly with cutaneous or neurological symptoms suggesting that there may be ethnic variance versus diagnostic bias in the previous report.  Laboratories are helpful for elevated beta-2 microglobulin present in more than 80%.  In summary, I learnt that if I suspect patient of having intravascular lymphoma in the brain, I will conduct a skin exam.  

Cefepime Encephalopathy

Motivation: My favorite fourth generation cephalosporin is cefepime.  Only a definite history of anaphylaxis to penicillins holds me back from prescribing cefepime.  More recently, I have met a few patients with confusion allegedly caused by cefepime.  Amazingly, stopping the cefepime improved the encephalopathy.

So, what is wrong with my favorite cephalosporin?  The literature on cefepime neurotoxicity is evolving and is still at the case report level.  Reviewed here is a case report and literature summary.

Paper: McNally, A., Pithie, A., and Jardine, D. "Cefepime: a rare cause of encephalopathy." Internal Medicine Journal (2012); 42 (6): 732-3.

Method: Case report and review of published literature.

Result: 
Case report:  A 70 year old woman after eleven days of cefepime for Pseudomonas osteomyelitis developed myoclonus and stupor.  Concurrently, patient also suffered from hepatic cirrhosis and acute on chronic renal failure.  For presumed drug toxicity, cefepime and all psychotropic drugs in patient's regimen (including morphine, gabapentin, oxazepam) were stopped.  Over three days, encephalopathy and myoclonus resolved.  Patient was re-challenged with cefepime at renal-adjusted dose.  Encephalopathy and myoclonus recurred in the next two days despite now resolved renal failure and normal ammonia.  Cefepime was stopped, and patient's encephalopathy cleared.

Literature Review: Eetrospective review of 42 cases showed that encephalopathy consisted of temporospatial disorientation (96%), myoclonus (33%), and seizures (13%).  The clearest association of cefepime toxicity exists with renal impairment though cefepime toxicity has also been described in patients with normal renal function.  The reported latency of symptoms from cefepime initiation is 1-10 days.  After stopping cefepime, symptoms regress over 2-7 days.

Discussion:
While the case for cefepime toxicity in this case report is weakened by concurrent hepatic and renal failure, the history of encephalopathy linked temporally with cefepime initiation along with improved mental clarity with cefepime cessation makes a good causal argument for cefepime causing encephalopathy.  There do not appear to be symptoms characteristic of cefepime neurotoxicity though seizures and myoclonus are frequent occurrences.    Without a larger case series, it is hard to attribute causality to cefepime.  On the other hand, if a patient with renal failure on cefepime develops confusion, I would recommend cefepime cessation (despite my personal attachment to the drug).