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).