Jordana Bieze Foster

In many ways, the frustration experienced bypatients struggling with mild cognitive impairment(MCI) is matched by the frustration ofclinicians facing the challenge of managing thisheterogeneous condition. The prognosis can bevariable, and no proven therapies exist.

Would it be less frustrating if a diagnosis of MCI could definitively identify patients who would eventually progress to Alzheimer disease (AD) or another form of dementia? What if identifying those patients would allow for early therapeutic intervention that would delay or prevent that progression? In reality, although dementia does ultimately develop in the majority of patients with MCI, little is known about how quickly MCI progresses to dementia. Some population-based studies suggest that as many as 44% of patients who meet diagnostic criteria for MCI will no longer meet those criteria on follow-up examination.

 To date, no therapies are approved specifically for use in patients with MCI, and the few clinical trials that have included patients with MCI have yielded little more than promising trends.

In practice, these clinical unknowns must be balanced against the very real possibility that MCI will progress to dementia. This necessitates an approach to patient care that is both delicate and diplomatic.

"You obviously want to be cautious about what you tell patients. You don't want to give them the impression that, for certain, they're going to get Alzheimer disease," said Allan I. Levey, MD, PhD, professor and chair of neurology at Emory University in Atlanta, and director of the Emory Alzheimer's Disease Research Center. "But it's also important to educate the patient about what MCI is and that it does carry a risk; that's the reality. People want to know what they can do, so it's our job to try to answer that question directly."

With so much ambiguity already surrounding MCI, ensuring an accurate diagnosis is essential. Although experts have preferences for different neuropsychological tests, most advocate a battery of tests that can distinguish MCI from normal age-related deficits of cognitive impairment and that can distinguish MCI from dementia by verifying that any influence on activities of daily living has not affected the patient's functional independence. All emphasize that because MCI is usually diagnosed in patients with whom the physician has no previous relationship, a thorough patient history-obtained from both the patient and his or her caregivers-can be as important as test results for making the diagnosis.

"Ideally, you're most sure of the diagnosis when not just the patient is aware of the problem, but another person also confirms that a problem exists, that it is new, and that it is getting progressively worse," said Martin R. Farlow, MD, professor of neurology at Indiana University School of Medicine in Indianapolis, and associate director of the Indiana Alzheimer Disease Center.

A relatively new development in the study and management of MCI is the concept of narrowing the diagnosis to 1 of 4 subtypes: amnestic or nonamnestic, and affecting 1 or multiple cognitive domains. Before a 2003 international conference in Stockholm at which the narrower subtypes were outlined,

 discussion of MCI was largely focused on memory impairment and the amnestic subtype.

The amnestic subtype is considered to be the potential precursor to AD, with conversion rates estimated at 10% to 15% per year. Although it was initially thought that amnestic MCI would progress to AD and nonamnestic MCI would progress to other forms of dementia, more recent research

 suggests that there is quite a bit of crossover between the subtypes and their outcomes, further complicating the clinical picture.

"The [documented] conversion rates are most clear for the amnestic subtype. So in my practice, if someone meets those criteria, I'm able to give them pretty reliable information about conversion rates-that there is an approximately 50% chance of conversion to AD within 5 years," Levey said. "If the patient is not amnestic, it encourages me to look for other causes of cognitive deficits."

Those other causes can include underlying cerebrovascular disease, sleep apnea or other sleep disorders, and behavioral issues, such as depression-conditions that, perhaps ironically, may be managed more successfully than amnestic disorders. To assist in the differential diagnosis, some clinicians advocate performing an MRI scan on any patient with suspected MCI. Research also suggests that different patterns of medial temporal lobe atrophy on MRI can differentiate MCI subtypes

 and can predict progression, particularly to AD.

"In my practice I get an MRI on anyone with objective memory loss," said Ranjan Duara, MD, medical director of the Wien Center for Alzheimer's Disease and Memory Disorders at Mount Sinai Medical Center in Miami Beach, Florida, and associate professor of medicine at the University of Miami. "If the MRI clarifies that the person doesn't have an underlying neurological condition, then that can be helpful in identifying other factors. You might find out that there are psychiatric or medical issues, or use of medications or alcohol that you didn't know about."

Unfortunately, even with an accurate diagnosis, the therapeutic options for MCI are limited. Few drugs approved by the FDA for mild to moderate AD have been studied in patients with MCI. Although the acetylcholinesterase inhibitor donepezil (Aricept) was associated with delayed conversion to AD in the first 12 months of the 2005 Memory Impairment Study,

 the statistically significant between-group difference in conversion rate had dissolved by the end of the 3-year study.

Researchers, nonetheless, have been encouraged by the results of the study, not only because of the early success in the entire group treated with donepezil, but also because the results showed even stronger evidence of the drug's effectiveness in carriers of apolipoprotein (APOE) e4 alleles, which have been associated with more rapid progression from amnestic MCI to AD.

Of the 769 patients with amnestic MCI in the study, possible or probable AD developed after 12 months in only 16 of the 253 patients who received donepezil (5 mg/d, increased to 10 mg/d after 6 weeks), compared with 33 of the 257 patients who received vitamin E (1000 IU daily, increased to 2000 IU daily after 6 weeks) and 38 of the 259 patients who received placebo. Although the conversion rates for the 3 treatment groups were not significantly different at 3 years, when researchers looked specifically at patients who tested positive for the APOE e4 allele, the conversion rate in the donepezil group was significantly lower than in the placebo group for the entire study period.

An MRI analysis of a 131- patient subset of that study population, published in 2007, found that treatment had no effect on annual percent-volume change in the hippocampus, entorhinal cortex, whole brain, and ventricle; however, the researchers did report a non-significant trend suggesting reduced hippocampal atrophy in APOE e4 allele carriers treated with donepezil.

An earlier, smaller-scale trial of donepezil also failed to demonstrate efficacy in its primary end points and improvement on the New York University (NYU) Paragraph Recall Test and the Clinical Global Impression of Change scale in the intent-to-treat population.

 In that 24-week trial, the 133 patients with amnestic MCI who were randomly selected to receive donepezil (5 mg/d for 42 days, increased to 10 mg/d) were significantly more likely to demonstrate improvement on the cognitive subscale of the AD Assessment Scale than were the 137 patients who received placebo.

Other drugs that are FDA- approved for mild to moderate AD have fared less well in clinical trials of the MCI population. The most recent trial to be published, the Investigation into the Delay to Diagnosis of AD with Exelon (InDDEx) study,

 found no significant benefit of the cholinesterase inhibitor rivastigmine (Exelon) on the time to clinical diagnosis of AD in more than 1000 patients with MCI. During the 48-month study, AD was diagnosed in 17.3% of patients who were randomly selected to receive rivastigmine (0.5 mg bid, gradually increased to a maximum of 12 mg/d) and in 21.4% of those who received placebo.

Researchers also found no significant between-group differences regarding change from baseline in performance on neuropsychological tests. Interestingly, treatment benefits were not seen even in a subpopulation of APOE e4 allele carriers. However, the authors noted that their inclusion criteria from the NYU Delayed Paragraph Recall Test were not adjusted for age and education. By contrast, delayed recall inclusion criteria for the Memory Impairment Study were adjusted for education level.

Two earlier studies of the cholinesterase inhibitor galantamine (Razadyne),

 which is also FDA-approved for mild to moderate AD, found no statistically significant benefits at 24 months in improving cognition or delaying conversion to AD in an MCI population of more than 1000 patients. Some statistically significant treatment-related differences were seen in population subgroups based on NYU delayed or immediate recall test performance.

Of 898 persons who underwent MRI, those randomly selected to receive galantamine (4 mg bid for 4 weeks, gradually increased to 8 mg or 12 mg bid) had significantly lower rates of whole brain atrophy than those who received placebo. Hippocampal atrophy rates were not significantly different.

An additional concern regarding the use of cholinesterase inhibitors in patients with MCI is the number of adverse events reported in the aforementioned clinical trials. In all trials, adverse events, primarily GI, occurred more frequently in treatment groups than in placebo groups. In the galantamine trials, more deaths caused by treatment-emergent adverse events occurred in patients taking the drug than in those taking placebo, although that imbalance was normalized to some extent when retrieved dropout patients were included in the analysis.

Despite the lack of efficacy of cholinesterase inhibitors in primary trial outcomes thus far, clinicians and researchers are encouraged by the secondary findings. Some are including the drugs in discussions of therapeutic options for patients with MCI who are willing to pay out-of-pocket.

"There have been a number of trials, and many have been negative, but there are also trials that have suggested that some of the medications developed for AD may have some limited but real utility in treating the memory deficits associated with at least the amnestic form of MCI for a period of time," Farlow said.

Similar results-falling short of efficacy regarding a primary end point but suggesting promise in other measures-were seen in a 2004 phase 2 trial of the γ-aminobutyric acid-B receptor antagonist SGS742 in 110 patients with MCI.

 After 8 weeks of treatment, no statistically significant difference in improvement on the Hopkins Verbal Learning Test-Revised was seen between patients who received SGS742 and those who received placebo. However, the test group did demonstrate greater improvement on the NYU Paragraph Recall Test, the Weschler Adult Intelligence Scale Digit Symbol test, and the Cambridge Automated Neuropsychological Test Battery.

Also in 2004, a 4-week trial in which 175 patients with MCI were randomly selected to receive either placebo or the ampakine compound, CX516, failed to demonstrate improvement in delayed recall of a 15-item word list.

 A treatment effect of CX516 was seen, however, in those patients with the greatest degree of memory impairment at baseline. A French safety and efficacy trial of a more potent ampakine compound, S18986, is currently recruiting patients with MCI.

The anti-inflammatory agent rofecoxib (Vioxx), which was FDA- approved for treatment of osteoarthritis and rheumatoid arthritis before being voluntarily withdrawn in 2004 in the wake of concerns about adverse cardiovascular events, was associated with statistically insignificant treatment benefits in a 2005 randomized controlled trial of 1457 patients with MCI.

 Although unexpectedly low in both placebo and treatment groups, the conversion rate was higher in the rofecoxib group (6.4%) than in the placebo group (4.5%). Secondary end points also did not differ significantly between groups.

Several trials of other potential MCI therapies-including the diabetes drug rosiglitazone (Avandia), nicotine, and physical exercise-are currently under way. Many suspect, however, that the best outlook for patients with MCI will follow the FDA approval of 2 next-generation, disease-modifying AD drugs: tramiprosate (Alzhemed), which works to prevent amyloid from forming plaque; and R-flurbiprofen (Flurizan), which lowers levels of toxic ß-amyloid 42. Tramiprosate was designated as a fast-track product by the FDA in July 2007; however, updated phase 3 clinical trials data were still pending at press time. R-flurbiprofen phase 3 data are expected to be released in 2008.

In the meantime, because pharmacotherapeutic options for patients with MCI are limited, clinicians are focusing on treating patients' symptoms while monitoring their cognitive function. It is recommended that, in particular, patients should be treated for cardiovascular disease and depression and other behavioral disorders that complicate and exacerbate cognitive impairment.

"We should put this into the context of optimal aging: how can you optimize the aging process-especially cognitive aging-and what are the things that can protect you?" Duara said. "The big factors are lifestyle changes that optimize your ability to age successfully. That's the way I approach MCI, lacking any treatment."

Without any definitive data in support of MCI therapies, clinicians looking to provide their patients with factual information may be equally frustrated by the variability in published conversion rates. A recently published study from the University of Pittsburgh

 found that 51% of 136 patients with MCI progressed to dementia after a mean of 4.3 years, which is consistent with some previous studies conducted in referral clinics

; however, epidemiological studies have reported conversion rates ranging widely-from 3.5% after 2 years of follow-up

 In the Pittsburgh study, 18% of patients with MCI returned to normal; in earlier studies, that figure ranged from 15% to 44%.

Some of this variability is related to how MCI is being defined, and some of it is related to the populations being studied. "If someone comes into a memory disorder clinic or an AD center, the likelihood that the person just walking through the door has AD is about 80%. Someone probably brought him or her there and has been observing the person," Duara said. "If you're doing an epidemiological survey, and you find out that 5% of people over age 65 have MCI and that some of those people go back to normal, that's not surprising. Those persons didn't have dementing disease. So when you compare studies, you have to consider that the diagnosis or the rate of progression from MCI to dementia is determined by the likelihood that the patients actually have a dementia."

It is not only difficult to predict whether and how quickly MCI will progress but it also appears equally difficult to predict the outcome of progression. Although it has generally been thought that amnestic forms of MCI progress to AD and nonamnestic forms to other types of dementia, research from Vienna and from Leipzig, Germany, suggest that this is not necessarily the case.

 In the Austrian study, 26.8% of nonamnestic and 48.7% of amnestic patients converted to AD within 30 months. Several patients with amnestic MCI also went on to convert to vascular dementia or Lewy body dementia.

In the German community-based study of 980 nondemented persons, patients with nonamnestic-single domain MCI were more likely to progress to AD than to vascular or other dementias. However, those patients with nonamnestic-multiple domain MCI were the most likely to progress to non-AD dementias.

Despite all that is not yet known about MCI and despite the lack of available therapies, clinicians agree that making the diagnosis can be valuable.

"We often overlook how distressing memory impairment is to the patient and his or her family, how long it takes to get a diagnosis, and how infrequently primary care doctors arrive at a diagnosis in the early stages of dementia," Levey said. "Patients may seem to circle around the health care system for years looking for answers. You're doing good things by making an accurate early diagnosis."

An early diagnosis gives patients time to make decisions about the future of their care in the event that the disease does progress. It also gives them the opportunity to maximize the effect of any lifestyle changes they may make or any promising therapies they may be willing to try.

"This is exactly the stage when you want to start intervention," Farlow said. "In that sense, it is good to start seeing symptoms at this stage, when there is a possibility of a reversible cause."

 Palmer K, Fratiglioni L, Windblad B. What is mild cognitive impairment? Variations in definitions and evolution of nondemented persons with cognitive impairment. 

 Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. 

 Jack CR, Petersen RC, Grundman M, et al. Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI. 

 Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. 

 Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. 

 Scheltens P, Fox NC, Barkhof F, Gold M. Effect of galantamine treatment on brain atrophy as assessed by MRI in patients with mild cognitive impairment. In: Program and abstracts of the 9th International Conference on Alzheimer's Disease and Related Disorders; July 17-22, 2004; Philadelphia. Abstract P2-158.
  

 Gold M, Nye JS, Goldstein HR, Truyen L. Initial evaluation of galantamine for mild cognitive impairment: results from two double-blind, randomized, placebo-controlled studies. In: Program and abstracts of the 9th International Conference on Alzheimer's Disease and Related Disorders; July 17-22, 2004; Philadelphia. Hot Topics Presentation S5-04.
  

 Tomlinson J, Cummins H, Wendt J, et al. SGS742, a novel GABAB receptor antagonist, improves cognition in patients with mild cognitive impairment. 

 2004;62(suppl 5). Abstract P02.053:A128.
  

 Cortex Pharmaceuticals Ampakine® fixed-dose CX516 cross national study of mild cognitive impairment (MCI) fails to meet primary end- point. Press release. Available at: 

http://www. cortexpharm.com/html/news/04/02-1704.html

 Johnson SA, Simmon VF. Randomized, double-blind, placebo-controlled international clinical trial of the ampakine CX516 in elderly participants with mild cognitive impairment: a progress report. 

 Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind study of rofecoxib in patients with mild cognitive impairment. 

 Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. 

 Petersen RC. Mild cognitive impairment as a diagnostic entity.

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 Fischer P, Jungwirth S, Zehetmayer S, et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. 

Articles

Managing MCI: Sifting Through the Unknowns

The temporary withdrawal of natalizumab(Tysabri) from the market in February 2005 inresponse to 3 cases of progressive multifocalleukoencephalopathy (PML) among clinical trial participantswas a wake-up call for the neurology communityabout the risks of therapies for multiple sclerosis(MS). Although natalizumab returned to themarket under a restricted distribution program inJune 2006, the impact of the withdrawal remains evidentin the more guarded optimism now being expressedby clinicians and researchers about the agentand about other immunosuppressive therapies for relapsing-remitting MS (RRMS) in the absence of longtermsafety data.

Such caution was readily apparent at the annualmeeting of the American Academy of Neurology(AAN) that took place in Boston from April 28 to May5. Phase 2 trial results suggesting dramatic reductionsin relapse rates and disability associated with themonoclonal antibody alemtuzumab (Campath)

were offset by presentations on the risks of thyroidabnormalities

 and immune thrombocytopenic purpura(ITP)

 for patients taking the drug. Phase 2 trialevidence in support of another monoclonal antibody,rituximab (Rituxan),

 seemed somewhat less encouragingin light of the eerily familiar December alert issuedby the FDA regarding 2 cases of PML in patientswith systemic lupus erythematosus who had beentreated with the drug. In several symposia on MS therapy,speakers cited the therapeutic potential of otherimmunosuppressive agents but cautioned that it isstill too soon to know just what types of adverse effectsthe agents might have.

"We are looking . . . [at] some very exciting times forbeing able to treat these patients," said Elliot M. Frohman,MD, PhD, director of the Multiple Sclerosis Programand the Multiple Sclerosis Clinical Center at theUniversity of Texas Southwestern Medical Center inDallas, who spoke during a symposium titled "HotTopics in Multiple Sclerosis" at the AAN meeting."But we may be reaching the ceiling of our ability totreat patients without compromising surveillance," hesaid.


 Not only must clinicians who treat patients with MSwrestle with the uncertainties about drug-relatedcomplications, they must do so on behalf of patientswho have a prognosis so daunting that they may bewilling to accept a high degree of risk in exchange fortherapeutic benefit. In an attempt to quantify patients'risk tolerance, researchers from the Cleveland Clinicsurveyed 128 patients who had planned to begin takingnatalizumab before its withdrawal. Because 2 ofthe aforementioned PML cases in natalizumab trialswere fatal, the survey focused on what patients consideredan acceptable risk of death in exchange for symptomrelief, delayed disease progression, or cure.

The survey results, presented at the AAN meeting,confirm what many neurologists have reported anecdotally.Although 18% of patients said that they wereunwilling to accept any risk of death, 14% said thatthey would accept a risk as high as 1-in-2 in exchangefor a cure. Patients in the Cleveland Clinic study saidthey would be willing to accept a risk of death of 1 in1000 in exchange for a two-thirds reduction in relapserate and a 42% slowing of disability rate, which werethe mean response rates that were reported in thephase 3 AFFIRM (Natalizumab Safety and Efficacy inRelapsing-Remitting MS) trial.

 Those who expressedthe highest levels of risk tolerance were those withhigh levels of disability, low self-reported quality oflife, and no dependents at home. The Cleveland Clinicstudy, of course, was focused on a single potentialcomplication of a particular drug in patients who hadreason to believe that the drug would help them;other patients with MS may have different levels ofrisk tolerance for other drugs associated with otheradverse effects. But physicians acknowledge that theydon't always see eye to eye with patients about whatconstitutes an acceptable level of risk.

"I think it depends on the patient's perception ofhow they're doing," said Patricia K. Coyle, MD, professorand acting chair of neurology at Stony BrookUniversity Medical Center and director of the StonyBrook Multiple Sclerosis Comprehensive Care Centerin Stony Brook, New York. "A patient with MS who isclearly deteriorating as far as she's concerned and isnot responding to treatment is generally willing totake greater risk than someone who is feeling well."


 Since its withdrawal in 2005, natalizumab has come tosymbolize the risks associated with immunosuppressiveMS therapy-although interestingly, some researcherssuspect that the risk of PML associated withnatalizumab actually may not be related to diminishedimmunosurveillance.

 The FDA authorized thedrug's return to market in June 2006 under specificconditions.

Because the clinical trial in which PML developedin 2 patients involved combination natalizumab andinterferon beta 1a (IFN-β-1a, Avonex) therapy,

 natalizumabwas to be used solely as a monotherapy. Itwas approved only for use in patients who had failedor who were ineligible for first-line treatment with interferonsor glatiramer acetate (Copaxone), and it onlymay be used by physicians and patients who enrolledin the Tysabri Outreach: Unified Commitmentto Health (TOUCH) risk-management program,which emphasizes physician training, patient education,and periodic monitoring. Beyond the 3 cases thatled to the drug's withdrawal (1 of which occurred ina patient with Crohn disease rather than with MS),no additional cases of PML have been reported in patientstaking natalizumab.

Meanwhile, evidence of the drug's clinical benefitscontinues to accumulate. The AFFIRM trial investigatorsrecently reported10 on 2-year MRI outcomes forpatients taking natalizumab versus outcomes forthose taking placebo. This report provided more detailthan the initial report on the AFFIRM trial.

Among the more recent findings were a 76% decreasein number of new lesions that were hypointenseon T1-weighted scans relative to the number ofnew lesions in patients taking placebo, a 9.4% decreasein median T2-weighted hyperintense lesion volume(vs an 8.8% increase in the placebo group), and a23.5% decrease in median T1-weighted hypointenselesion volume (vs a 1.5% decrease in the placebogroup).

Researchers from the AFFIRM and SENTINEL(Safety and Efficacy of Natalizumab in Combinationwith Avonex) trials reported that natalizumab was associatedwith significantly reduced levels of visionloss.

 In the AFFIRM patient population, those takingnatalizumab were 35% less likely than those takingplacebo to experience clinically significant vision loss(defined as a 2-line worsening of visual acuity score)at a contrast level of 1.25%. In the SENTINEL studypopulation, the risk was reduced by 28% for those takingnatalizumab plus IFN-β-1a compared with thosetaking IFN-β-1a alone.

Further analysis of the AFFIRM vision data, presentedat the AAN meeting,12 found that even patientsconsidered treatment failures-those who experienced12 weeks of sustained disability progression asmeasured using the Expanded Disability StatusScale-were significantly less likely to suffer concurrentvision loss if they were treated with natalizumabthan with placebo.

The clinical benefits associated with natalizumab,in turn, improve patients' quality of life, according toanother analysis of both the AFFIRM and SENTINELdata presented at the AAN meeting.

 In the AFFIRMtrial, patients treated with natalizumab were significantlymore likely than those in the placebo group toexperience clinically important improvement (achange of 0.5 SDs) on the physical component summaryof the Short Form-36 (SF-36) health survey after104 weeks. In the SENTINEL trial, those who receivedcombination therapy were more likely to experience asimilar degree of improvement than those treatedwith IFN-β-1a alone. Natalizumab also was associatedwith trends toward significant improvement on themental component summary of the SF-36. Contributingto improvements in quality of life may be issues ofconvenience; natalizumab is administered only onceper month, whereas other drugs require several injectionsor more per week.

Still, despite all of the positives, any professionaldiscussion of natalizumab inevitably returns to therisk of PML-which is of particular concern becausethe differential diagnosis of PML in patients with MSis so difficult.

"PML produces lesions of brain and neurologicalabnormalities that can be very hard to sort out fromMS, at least early on," Coyle said.

Frohman, for one, said he does not consider natalizumabto be the best treatment option for patients whohave failed interferons or glatiramer acetate.

"I'm very cautious," he said. "I have to ask myself,if this were my wife or my daughter, would I treatthem with this drug?"


 Of the drugs currently FDA-approved for RRMS, theone that is often included with natalizumab in discussionsabout risk and benefit is the chemotherapeuticagent mitoxantrone, which was approved in June 1999for treatment of worsening RRMS and in October 2000for secondary progressive MS. Because of risks of cardiotoxicity,myelosuppression, and leukemia, dosingwith mitoxantrone must be limited to 140 mg/m2,which is the equivalent of 2 to 3 years of therapy.

Recent therapeutic approaches have involved combiningmitoxantrone with glatiramer acetate to, in part,reduce the mitoxantrone dose, thus reducing the riskof complications.

 A multicenter team of researchersfrom Montreal; Phoenix; and Burlington, Vermont, reportedthat patients who received 3 monthly infusionsof mitoxantrone (36 mg/m2 total) followed by 12.5months of daily dosing with glatiramer acetate experienceda 70% decrease in gadolinium-enhancing lesionson MRI at 15 months compared with patients who weretreated with glatiramer acetate alone. However, researchersand clinicians are somewhat wary of combinationtherapies for MS because both PML cases in thenatalizumab trials occurred in patients receiving combinationtherapy, and MS in patients treated withatorvastatin (Lipitor) in combination with subcutaneousIFN-β-1a (Rebif) unexpectedly worsened, whichwas reported at the AAN meeting.

Infertility is another concern when treating patientswith chemotherapeutic agents such as mitoxantrone oroff-label cyclophosphamide, particularly because patientswith MS tend to be relatively young when thediagnosis is made. Interventions such as cryopreservationof sperm or embryos are viable options but needto be part of the overall treatment plan, according toMichael Glantz, MD, associate professor of neurologyat the University of Massachusetts in Worcester, whospoke at an AAN symposium on immunosuppressivetherapy for demyelinating disease.

"Because fertility intervention delays treatment, it'simportant to talk about it early on," Glantz said.


Taking at least some of the attention away from natalizumabin the risk-benefit discussion are the recent incidencesof adverse events associated with the monoclonalagents alemtuzumab and rituximab. Alemtuzumabwas approved by the FDA in May 2001 fortreatment of B-cell chronic lymphocytic leukemia. TheCAMMS223 phase 2 trial of alemtuzumab in patientswith RRMS was suspended in September 2005 after 3cases of ITP-characterized by low platelet counts andincreased risk of hemorrhage-were diagnosed; subsequentscreening by the study investigators identified3 more patients with the disorder. The first patientin whom ITP developed did not seek treatment for 2weeks despite experiencing symptoms and ultimatelydied, but the other 5 cases resolved successfully, accordingto Herman Sullivan, MD, a neurologist withMichigan Medical in Grand Rapids, who describedthe trial's ITP screening and treatment protocols at theAAN meeting.

 Four of the 5 patients were treatedwith corticosteroids, while the fifth received no treatment;as of early May, all had been stable for 5 to 13months.

CAMMS223 researchers also found that thyroidrelatedadverse events at 2 years occurred in 11.1% ofpatients treated with alemtuzumab but only in 1.9% ofthose treated with IFN-β-1a.

 However, the 2-yearrates of thyroid-related complications were muchlower than in previous studies, in which antibodiesagainst the thyrotropin receptor and autoimmune hyperthyroidismdeveloped in as many as a third of patientsat 18 months.

As with natalizumab, the risk of potentially fatalcomplications associated with alemtuzumab offsetwhat were otherwise extremely encouraging clinicaltrial results initially presented this past September atthe 22nd Congress of the European Committee forTreatment and Research in Multiple Sclerosis inMadrid and presented again at the AAN meeting.

 In334 treatment-naive patients with RRMS, those treatedwith alemtuzumab had a 75% lower risk of relapseand a 65% lower risk of sustained disability at 2 yearscompared with those treated with IFN-β-1a.

In an open-label, single-arm study of patients withRRMS in whom interferon treatment had failed, EdwardJ. Fox, MD, PhD, director of the MS Clinic of CentralTexas in Austin, and colleagues found that 71.7% ofpatients were relapse-free at 2 years, and the annualizedrelapse rate dropped from 1.6 for the 2 years precedingthe study to 0.2 at the 2-year follow-up.

In terms of convenience, alemtuzumab is evenmore attractive than natalizumab. Dosing regimens intrials have involved an initial 5-day course of daily injectionsfollowed by a 3-day course 1 year later.

"It's given for a couple of days, and then you don'tgive it again for a year, which is pretty doggone convenient,"Coyle said. "The phase 2 trial had good results,with low rates of relapse and disability comparedwith a very active agent. But there isn't a hugeexperience with long-term treatment."


The monoclonal agent rituximab, which is FDAapprovedfor treatment of non-Hodgkin lymphomaand for refractory rheumatoid arthritis, took a hit inthe public relations department in December with therelease of an FDA warning following 2 deaths fromPML in patients with systemic lupus erythematosuswho were being treated with the drug. However, perhapsbecause of physicians' lengthy experience withrituximab for other indications, the warning has doneless to distract from the drug's potential benefits fortreating MS than might have been expected.

Those potential benefits were described at the AANmeeting by Stephen Hauser, MD, professor and chairmanof neurology at the University of California SanFrancisco. In a phase 2 trial, Hauser and colleaguesfound that the 69 patients with RRMS treated with rituximabhad a 91% reduction in gadolinium-enhancinglesions on MRI and a 58% reduction in relapse raterelative to the 35 patients treated with placebo.5 Butwith a humanized version of the chimeric rituximabprojected to be available by 2009, the relative risks andbenefits of rituximab may ultimately be less importantthan those of some other agents currently in trials.


In the next generation of MS drugs, oral formulationsare most likely to appeal to patients because of theirconvenience. Recent studies of 2 oral MS drugs, fingolimodand fumarate, were mixed in relation to bothsides of the risk-benefit equation.

A 255-patient, European multicenter proof-of-conceptstudy published last fall in the 

 reported that the annualized relapserate for patients with RRMS treated with 1.25 mg/d or5 mg/d of fingolimod for 6 months was about halfthat for patients given placebo. The median total numberof gadolinium-enhancing lesions on MRI in bothdosage groups also was significantly lower than in theplacebo group. However, 2 serious infections were reportedin the active-treatment groups, and 1 patient inthe high-dose group developed posterior reversibleencephalopathy syndrome. Fingolimod also was associatedwith increased alanine aminotransferase levelsand a transient decline in heart rate of several hours'duration following the first dose.

The oral fumarate agent BG-12 has relatively fewsafety concerns, but its phase 2 efficacy data are lessremarkable than some other MS agents in development.In a European trial in which 257 patients withRRMS were randomly selected to receive 1 of 3 dosesof oral fumarate or placebo, the most common adverseevents in the treatment groups were flushing, GI disorders,headache, and nasopharyngitis.20 The 64 patientswho received the highest dose (240 mg, 3 timesdaily) had a 69% reduction in the mean number ofnew gadolinium-enhancing lesions on MRI and a 48%reduction in new or enlarging T2-weighted hyperintenselesions at 6 months compared with patientswho received placebo.21 The researchers also reporteda 32% reduction in relapse rates for the high-dosegroup compared with the placebo group, but that differencewas not statistically significant.

Two phase 3 trials of BG-12 are currently ongoing:one in which patients will be randomly selected toreceive either BG-12 or placebo, and another in whichpatients also will be randomly selected to receiveglatiramer acetate.


Unfortunately for clinicians already dealing with thechallenges of managing this heterogeneous patientpopulation, there appears to be no single right answerto the risk-benefit equation. Fortunately, the most effectivemeans of finding the right answer for each patientinvolves a skill that also pays dividends in otheraspects of MS care: communication.

"I believe in an informed patient," Coyle said. "Themore knowledgeable the patient, the better."

Because there is a limit to the frequency with whicha patient can realistically be screened for potential adverseevents, educating patients about the risks associatedwith any treatment and maintaining an openline of communication helps maximize the chance thatpotentially serious symptoms will be reported and addressedearly. Including a family member or othercaregiver in discussions also can be helpful.

"You definitely need the patient's input," said AnjaliShah, MD, assistant professor of neurology andphysical medicine and rehabilitation at the Universityof Texas Southwestern Medical School and directorof multiple sclerosis neurorehabilitation at the MultipleSclerosis Clinical Center in Dallas. "An office visitis sterile. You're not seeing the patient at home, or atwork," she said.

Clinicians who can clearly explain their professionalopinions about the risks and benefits of a particulartherapy also can help keep patients' expectations incheck. But being sensitive to the patient's perspectiveis important too. "They're the ones who have the disease,"Shah said. "I never close the door but insteadtry to propose a stepwise approach."

 Alter M, Halpern L, Kurland LT, et al. Multiple sclerosis in Israel. Prevalence among immigrants and native inhabitants. 

 Dean G. Annual incidence, prevalence, and mortality of multiple sclerosis in white South African-born and in white immigrants to South Africa. 

 Gale CR, Martyn CN. Migrant studies in multiple sclerosis. 

 Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. 

 Dean G, McLoughlin H, Brady R, et al. Multiple sclerosis among immigrants in Greater London. 

 Elian M, Dean G. Multiple sclerosis among the United Kingdom-born children of immigrants from the West Indies. 

 Elian M, Nightingale S, Dean G. Multiple sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies.

 Kurtzke JF, Beebe GW, Norman JE. Epidemiology of multiple sclerosis in US veterans, III: migration and the risk of MS.

 Hernan MA, Olek MJ, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. 

 Goldberg P. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence (a viewpoint). Part 1: Sunlight, dietary factors and epidemiology. 

 Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. 

 Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. 

 Freedman DM, Dosemeci M, Alavanja MC. Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates. 

 van der Mei IA, Ponsonby AL, Dwyer T, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. 

 Hammond SR, McLeod JG, Macaskill P, English DR. Multiple sclerosis in Australia: socioeconomic factors. 

The temporary withdrawal of natalizumab (Tysabri) from the market in February 2005 in response to 3 cases of progressive multifocal leukoencephalopathy (PML) among clinical trial participants was a wake-up call for the neurology community about the risks of therapies for multiple sclerosis (MS). Although natalizumab returned to the market under a restricted distribution program in June 2006, the impact of the withdrawal remains evident in the more guarded optimism now being expressed by clinicians and researchers about the agent and about other immunosuppressive therapies for relapsing- remitting MS (RRMS) in the absence of longterm safety data.

Trying Times: Factoring Risk-Benefit Equations Into MS Therapeutics

For years experts in multiple sclerosis (MS) have been touting the potential benefits of combination therapies for controlling disease progression. The difficulty in finding just the right combination, however, was evident in the mixed nature of findings presented at the Annual Meeting of the American Academy of Neurology (AAN) in Boston, April 28 to May 5.

Among the drugs being considered as adjuncts to existing MS therapies is the cholesterol-lowering agent atorvastatin (Lipitor). Researchers from the University of California, San Francisco, made headlines in March 2006 with the online publication of a study in which combined suboptimal dosages of atorvastatin (0.5 mg/ kg/d) and glatiramer acetate (Copaxone) (50 µg) were associated with clinical improvement and reduced inflammation in experimental murine models of MS.

 Findings reported at the AAN meeting, however, suggest that combining atorvastatin with subcutaneous interferon beta 1a (IFN-ß-1a; Rebif) in humans has the opposite effect.

Twenty-nine patients with relapsing-remitting (RR) MS who had been taking subcutaneous IFN-ß-1a for at least 6 months were randomly selected to receive 6 months of additional treatment with 40 or 80 mg/d of atorvastatin or placebo. Twenty-four patients completed the study. New and enhancing MRI lesions or clinical relapses were observed in 10 of the 15 patients who received the combination therapy (6 high dose, 4 low dose), but in only 1 of the 9 patients in the placebo group.

The results, which are consistent with those presented by the same group at the 2005 annual AAN meeting,

 may reflect an incompatibility specific to interferons. In vitro research from the University of Chicago, Illinois, also presented at the 2007 AAN meeting, suggests that statins block interferons' signaling pathways, thus decreasing their therapeutic efficacy.

Preliminary analysis of the Avonex Combination Trial (ACT) findings also failed to detect a statistically significant benefit for combining intramuscular IFN-ß-1a (Avonex) with either the chemotherapeutic agent methotrexate or the corticosteroid methylprednisolone.

 Previous studies have suggested that combining IFN-ß-1a with either methotrexate

 could reduce disease activity in patients with MS.

The ACT study included 313 patients with RRMS from 72 locations. Each patient had demonstrated breakthrough disease activity (relapse or new lesions on MRI) in the previous 12 months and after at least 6 months of treatment with intramuscular IFN-ß-1a. In addition to interferon therapy, patients were randomly selected to receive weekly oral methotrexate (20 mg), pulsed intravenous methylprednisolone (1000 mg/d for 3 days) every other month, both, or placebo.

After 12 months, patients on combination therapy had lower incidences of relapse and MRI lesions than those on monotherapy, with the 3-drug group showing the most favorable outcome. However, the differences between the 4 treatment groups did not achieve statistical significance, according to Jeffrey Cohen, MD, director of the experimental therapeutics program at the Cleveland Clinic's Mellen Center for MS Treatment and Research, and principal investigator of the ACT study.

Similarly, researchers from the University of Calgary, Alberta, found that 9 months of treatment with a combination of glatiramer acetate and the tetracycline derivative minocycline was associated with a trend toward improvement in the number of T1 enhancing lesions, new T2 lesions, and annualized relapse rate compared with treatment with glatiramer acetate and placebo.

 Again, the between-group differences were not statistically significant. Previous research in mice has supported the minocycline-glatiramer acetate combination for treatment of MS.

More encouraging results involved the peroxisome proliferator-activated receptor gamma agonist pioglitazone (Actos), currently FDA-approved for treatment of type-2 diabetes. In vitro and animal studies have suggested that the drug also may have anti-inflammatory benefits in patients with MS.

 Researchers from the University of Illinois at Chicago randomly assigned 22 patients currently taking IFN-ß-1a to also begin a course of either 30 mg/d pioglitazone or placebo for 1 year.

The investigators found that lesion volume decreased by 7% from baseline in patients taking pioglitazone but increased by 3% in patients taking placebo. Significantly less gray-matter atrophy was observed in the pioglitazone group compared with the placebo group (3.1% loss vs 5.8% loss).

Researchers from the University of Rochester, New York, reported that functional benefits were observed in a phase 3 trial of the potassium channel blocker fampiridine, administered as adjunctive therapy.

 A clinical response was seen after 14 weeks in 34.8% of the patients who were randomly assigned to receive fampiridine compared with 8.3% patients assigned to receive placebo. Responders in the fampiridine group demonstrated a 25% improvement in walking speed from baseline.

Research related through poster presentations at the AAN meeting support the short-term use of the chemotherapeutic drugs mitoxantrone and cyclophosphamide in MS treatment regimens. Preliminary 2-year follow-up results of a randomized multicenter study revealed that a 90% reduction in MRI lesions could be achieved in patients who received 12.5 months of glatiramer acetate therapy followed by 3 monthly intravenous infusions of mitoxantrone. In comparison, a 70% reduction in MRI lesions was achieved in patients who received a 15-month course of glatiramer acetate monotherapy but no additional chemotherapy.

 Further analysis demonstrated significantly favorable outcomes for the combination-therapy group in terms of T1 and T2 lesion volume and proportion of enhancing lesions that evolved into chronic black holes.

Another study found that 6 months of cyclophosphamide, given as a monthly 1000-mg dose to patients in whom treatment with IFN-ß-1a or glatiramer acetate had failed, significantly reduced brain atrophy.

 In this study, a 1.3% decrease in cross-sectional normalized brain volume was observed at 3-year follow-up in 31 patients treated with cyclophosphamide. In comparison, a 2.7% decrease in brain volume was observed in 40 patients who received 6 to 12 months of monthly corticosteroids concurrent with IFN-ß-1a or glatiramer acetate therapy.   

 Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. 

 Birnbaum G, Altafullah I, Reder A. A double blind, placebo controlled trial of atorvastatin in combination with subcutaneous interferon beta 1a in persons with multiple sclerosis. 

 Birnbaum G, Altafullah I. A double blind, placebo controlled combination trial of interferon beta 1a (Rebif) and atorvastatin (Lipitor) in patients with relapsing-remitting multiple sclerosis. 

 Dhawan N, Reder A. Statins block interferon signaling in human immune cells: potential loss of the therapeutic effect of IFN-b in multiple sclerosis. 

 Cohen J, Calabresi P, Eickenhorst T, et al. Results of the Avonex Combination Trial (ACT). 

 Calabresi PA, Wilterdink JL, Rogg JM, et al. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. 

 Gasperini C, Pozzilli C, Bastianello S, et al. Effect of steroids on Gd- enhancing lesions before and during recombinant beta interferon 1a treatment in relapsing remitting multiple sclerosis. 

 Metz L, Li D, Traboulsee A, et al. Glatiramer acetate combined with minocycline reduces the number of T1 Gd-enhancing and new T2 lesions compared to glatiramer acetate alone. 

 Giuliani F, Fu SA, Metz LM, Yong VW. Effective combination of minocycline and interferon-beta in a model of multiple sclerosis.

 Klotz L, Schmidt M, Giese T, et al. Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients. 

 Kaiser C, Shukla D, Stebbins G, et al. Results of a phase I trial of pioglitazone in RRMS patients. 

 Goodman A, Schwid S, Brown T, et al. A phase 3, multi-center trial of oral, sustained-release fampiridine (4-aminopyridine) in multiple sclerosis. 

 Vollmer T, Campagnolo D, Panitch H, et al. Reductions in MRI disease activity and relapse rates observed after induction of shortterm immunosuppression with mitoxantrone followed by longterm glatiramer acetate (GA) are maintained at 24 months in patients with relapsing remitting multiple sclerosis (RRMS).

 Arnold DL, Bar-Or A, Freedman M, et al. Reductions in Gd enhancing lesions observed with glatiramer acetate following a brief and low dose course of mitoxantrone in patients with relapsing remitting multiple sclerosis (RRMS) are paralleled by favorable effects on MRI markers of disease burden and black hole evolution. 

 Boster A, Perumal J, Bao F, et al. Short-term exposure to cyclophosphamide is effective in reducing long-term brain atrophy in refractory RRMS. 

Combo Therapies for MS: In Trials, Some Pairings Fare Better Than Others

On December 8, 1995, Jean-Dominique Baubyshaved, dressed, drank a cup of hot chocolate,and spent the day conducting business as theeditor-in-chief of Elle magazine. By the end ofthat day, 43-year-old Bauby was in a coma,the result of a massive brain stem stroke.

One month later, Bauby had passed through several weeks of grogginess to become fully conscious--but was unable to speak or move. He had become a victim of locked-in syndrome (LIS). Once a powerful figure in the communications business, Bauby found himself unable to even signal for the attention of an attending nurse.

Chances are you've heard this story. But the reason you've heard it is because, in spite of it all, Bauby did find a way to communicate. Although it was a painstakingly slow process in which he would blink his left eyelid to choose letters from an alphabet board, Bauby spelled out his new life in the 132-page book 

 which was published shortly before his death in March 1997.

 Paradoxically, a method of communication--albeit rudimentary--was what persons in the medical community and around the world needed to appreciate the thoughts and feelings surging behind the silence and stillness of those who are locked in.

Physicians have learned from Bauby and other locked-in patients that the inability to communicate is far more frightening and debilitating than the inability to move. As a result, rehabilitation strategies for patients with LIS have focused on finding ways to facilitate communication using whatever means are available to a particular patient--whether blinking an eye, twitching a thumb, or even focusing one's thoughts to control a computer cursor with the help of a brain-computer interface (BCI). Clinicians believe that in the majority of cases, improved communication drastically improves patients' quality of life and allows them to be more actively involved with family and community. But some patients with LIS also have communicated feelings of frustration, depression, and even suicidality--thus sparking debate about what the quality of life for a locked-in patient really is and about the relative value of artificial ventilation and other expensive technologies used in sustaining their lives.	

The incidence of LIS is difficult to determine from the medical literature, in large part because it is often misdiagnosed as coma, vegetative state, or minimally conscious state. Between 1997 and 2004, the French-based Association du Locked-In Syndrome (ALIS) registered 367 patients with LIS in its database,

 which has served as the basis for much of the research that has been done on this patient population. Some believe that the actual number of patients with LIS is much higher than that represented by the database.

"Probably every general neurologist has one of these cases in their practice," said Andrew J. Haig, MD, associate professor of physical medicine and rehabilitation at the University of Michigan. "It's not as uncommon as you'd think."

In 1979, Austrian researchers categorized LIS into 3 subtypes: classic LIS, in which conscious patients are immobile except for eye movement; incomplete LIS, in which minimal amounts of residual movement have been preserved in parts of the body beside the eyes; and total LIS, in which patients are conscious but unable to move any muscles at all.

Although the Austrian terminology is used most often for classification of LIS, José Leon-Carrion, PhD, and colleagues at the University of Seville in 2002 suggested a different set of 3 subtypes: complete LIS, in which conscious patients may either be totally paralyzed or may have preserved eye movement as the result of a brain stem lesion; incomplete LIS, in which the patient may be able to perform other movements because of a partial recovery of the brain stem injury within a few weeks of LIS onset; and pseudo-LIS, in which the brain stem is secondarily affected by a primary cortical or cerebellar lesion.

As Leon-Carrion's classification system suggests, the most frequent cause of LIS is thought to be injury to the basis pontis or ventral pontine region of the brain stem. In a review of cases published in 1986, James R. Patterson, MD, and Martin Grabois, MD, of Baylor College of Medicine found that injury to the area of the ventral pons was the cause of LIS in 82 of the 139 cases examined.

The injury is most often vascular, a type cited in the literature as responsible for 52% to 100% of cases.

 In a recent analysis of 250 cases from the ALIS database, Steven Laureys, MD, PhD, a neurologist at the Cyclotron Research Centre and research associate for the Belgian Foundation for National Scientific Research in Liege, Belgium, found that 86% of patients had LIS of vascular origin.

 Brain stem lesions in LIS patients also may result from traumatic brain injury (TBI), which is cited as the cause in 9% to 31% of cases,

 or, infrequently, other causes ranging from brain tumor to prolonged hypoglycemia.

 Temporary LIS can be pharmacologically induced or stem from severe cases of peripheral polyneuropathy.

Of note, a completely locked-in state also can occur in the end stages of amyotrophic lateral sclerosis (ALS),

 a situation that presents a very different set of patient care challenges than those associated with stroke or TBI. Because the degenerative progression of the disease can be predicted with some accuracy, ALS patients, their caregivers, and their physicians are able to prepare for the locked-in state and practice alternative means of communication before they are left with no other options. In this sense, they are spared some of the emotional trauma of stroke patients, for example, who may be in a locked-in state for weeks, months, or even years before a physician or (more often) a family member becomes aware that the patient is in fact fully conscious.

However, ALS patients in a locked-in state have no hope of recovery; a patient who becomes locked in following a stroke or TBI is not likely to recover fully but at least can hope for small gains that could significantly improve quality of life.

At its most basic level, communication for locked-in patients involves a simple yes-no system based on eye movements. Some may use a system in which 1 eye blink means "yes" and 2 blinks means "no"; others may look up for "yes" and look down for "no."	

Low-tech methods also can be used, albeit slowly, for more detailed communication with any of several types of alphabet boards.

Jordana Bieze Foster

Articles

Managing MCI: Sifting Through the Unknowns

Trying Times: Factoring Risk-Benefit Equations Into MS Therapeutics

Combo Therapies for MS: In Trials, Some Pairings Fare Better Than Others

Locked-In Syndrome: Advances in Communication Spur Rehabilitation

Pain in SCI: Elusive Causes and Management Challenges

Racial, Ethnic Variables Shape the Experience of Chronic Pain