Marfan Syndrome Treatment & Management

The majority of medical therapy as it relates to MFS has been targeted at preventing cardiovascular compromise, which is the most likely cause of demise in this patient population.^{[12, 21, 14]} Beta-blockers and afterload reduction agents are used to reduce stress on the aortic and mitral valves and the aortic root.^[22]

Given that patients with MFS often have abnormal or prosthetic valves, all patients must receive routine antibiotic prophylaxis before undergoing procedures that could produce bacteremia. Researchers have demonstrated that the entire aorta, and especially the root, is stiffer than normal in patients with MFS.

Beta-blockers have been used in attempts to decrease the onset and rate of aortic root dilatation and dissection. Studies have demonstrated a synergistic effect with regard to the reduction of aortic stiffness, decreased vascular resistance, and improved cardiac compliance when nitroprusside and beta-blockers are used concomitantly.

Beta blockade is used because it is believed to reduce both inotropy and chronotropy and thus reduce the stress on the aortic root. Nitroprusside reduces overall systemic vascular resistance, which serves to reduce overall afterload and stress on the heart. Whether these effects translate into decreased morbidity and mortality at this time is unclear, as no long-term studies have been preformed yet. Calcium channel blockers (eg, verapamil) are being investigated to assess their effects on cardiovascular physiology in patients with MFS.

Scoliosis is the most common major skeletal deformity encountered in patients with MFS that requires intervention. No specific medicinal intervention exists to treat scoliosis. Nonoperative means of treatment (eg, bracing) may be attempted but are usually unsuccessful. Scoliosis occurs in approximately 50-70% of patients with MFS and differs from idiopathic adolescent scoliosis with regard to curve pattern, progression, and symptoms. The double right thoracic – left lumbar curve is the most common type among patients with MFS, whereas a single pattern is usually seen in the idiopathic type. Pelvic obliquity is uncommon in both types, however.

Unfortunately, these patients often have an earlier onset of scoliosis with severely rigid, painful, and deforming curves, as well as have a high incidence of curve progression. The curve progression may average 7-10° per year after the onset of scoliosis, and the curve often progresses rapidly in the early adolescent period during maximal vertebral growth. This is also in contrast to the idiopathic type, which is typically not painful and is not as progressively deforming as the scoliosis in patients with MFS. Scoliosis, in combination with poor musculature and chest deformities, can cause significant respiratory compromise, which mandates early detection and prevention, if possible, in this patient population.

Nonoperative intervention for the scoliosis typically involves observation followed by the use of a thoracolumbosacral orthosis (TLSO) if the curve is mild and reveals signs of progression. Bracing is controversial; many surgeons believe that the bulk of curves in patients with MFS progress regardless of bracing and thus require operative intervention to prevent worsening deformity.

For patients with curves less than 25°, observation and serial radiographs every 3-4 months is the recommended management. When the curve ranges from 25-40°, Milwaukee bracing or an underarm TLSO is used. This may be a bridge to future surgical intervention. Bracing is only used in patients with mild curves (ie, 25-40°) and no sagittal plane deformity (ie, thoracic lordosis or lumbar kyphosis). Bracing is not indicated for curves that are rigid, large, or have associated sagittal deformities.

Mitral valve regurgitation may become so severe that medical therapy must be replaced with surgical intervention. The mitral valve is often found to have a dilated annulus, redundant and flaccid cusps, and ruptured chordae tendineae. Mitral valve repair is undertaken if possible, to delay the eventual mitral valve replacement; this is done because these patients often present at a young age and may require further reconstructive surgery later. Surgical repair also preserves papillary muscle function and obviates chronic anticoagulation, unlike artificial valve replacement .

The ascending aorta (aortic root) or the incompetent aortic valve may also require repair. Either a composite graft or a valve-sparing technique is performed.^[23] The valve-sparing technique is usually performed in patients whose aorta has dilated to approximately 50 mm. Patients with widely dilated aortic roots or significantly attenuated aortic cusps typically undergo a composite graft repair. This is also the procedure of choice in the case of an acute aortic root dissection. Some surgeons advocate prophylactic composite grafting in patients who have a history of increasing aortic dilatation and a family history of sudden cardiovascular death.

The major indication for surgery for the musculoskeletal system involves progression of moderate to severe scoliosis. Chest-wall deformities may also be so severe that they impact cardiopulmonary mechanics; these can be surgically corrected as well. In the past, patients with MFS did not have these chest-wall deformities addressed, and most died at an early age due to intrinsic cardiovascular disease. The advent of successful aortic root surgery as well as aortic and mitral valve replacement has changed the overall long-term outlook for patients with the disease. Adequate treatment should be provided for those with scoliosis to reduce pain, to improve overall cosmetic appearance, and, most importantly, to improve pulmonary mechanics through reduction of spinal and chest-wall deformities.

As previously described, bracing can be considered in patients with mild curves (see the Medical therapy section). However, most patients with MFS will have significant curve progression that eventually warrants surgical intervention. Patients with curves greater than 40-50º or with associated abnormal sagittal curvature deformities require surgery. Posterior spinal fusion and segmental spinal instrumentation, along with autogenous bone grafting, are the mainstay of treatment. Most authors agree that scoliosis can be corrected with this approach; however, the overall incidence of complications varies in different series. Pseudoarthrosis and loss of correction can occur and are problematic; the incidence rates range from 12-40%.

Most authors recommend aggressive bone grafting, rigid internal fixation, and adequate patient surveillance postoperatively to diagnose complications early in the clinical course. Sagittal malalignment (kyphotic deformity) may require an anterior fusion (excision of discs) followed by posterior spinal fusion and segmental spinal instrumentation to achieve satisfactory correction of the sagittal alignment.

The most important aspect in the preoperative evaluation of patients with MFS is to rule out any imminent cardiac compromise. A complete cardiac workup, including electrocardiography followed by echocardiography, is mandatory. It is well known that aortic dilatation and subsequent rupture can develop throughout these patients' childhood and adult life; thus, one must be diligent to exclude these entities before any surgical undertaking. Any evidence of aortic dilatation must be treated medically or surgically before any spinal reconstruction is attempted.

See Surgical therapy.

Recent strides in the management of the cardiovascular manifestations of MFS have led to a significant decrease in the morbidity and mortality that are associated with this condition. Before the advent of pharmacologic and surgical therapy for aortic root and valvular disease, the life expectancy for patients with MFS was about two thirds that of the healthy population. Aortic dissection and congestive heart failure due to aortic and mitral valvular anomalies accounted for over 90% of the known causes of death.

Patient longevity now approaches that of persons without MFS, although cardiovascular compromise is still the most common cause of patient death, likely due to sudden death in the previously undiagnosed patient and a new diagnosis in those whose disease process has progressed beyond the scope of medical or surgical cure.

Many new areas of investigation into the etiology and effects of MFS exist. Some are ongoing, whereas others will likely come to the forefront as the disease is more readily understood.

• With regard to the skeletal system, investigators are seeking to discover new modalities by which to delay or reduce the progression of scoliosis and assess the effect of hypermobility on joint degeneration and deformity.
• Cardiovascular research has focused on trying to identify patients at risk for compromise as early as possible and to determine if medications other than beta-blockers are useful in terms of their cardioprotective effects.
• There are some preliminary data based on murine studies that indicate an angiotensin II receptor antagonist agent (eg, losartan) or transforming growth factor-beta neutralizing antibodies may have the potential to reverse some of the primary clinical manifestations in MFS, such as aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction.^[6]
• Researchers are also focusing on the effects of laser surgery on the cornea and lens, as well as the correction of cataracts and the preservation of sight.
• Genetic testing is particularly important. It is known that the FBN1 locus is associated with MFS; however, it is possible that other genes may cause a marfanoid habitus with phenotypic manifestations similar to those seen in MFS.^[24]

Although many discoveries have been made since the original description of MFS in 1896, much investigation is still needed.