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 Table of Contents  
Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 151-155

Part 4: Clinical management of an undiagnosed systemic condition

1 Department of Internal Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
2 Department of Anesthesiology, University of Pennsylvania, Philadelphia, PA, USA
3 Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, PA 18020, USA

Date of Web Publication7-Jul-2017

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801 Ostrum Street, Bethlehem, PA 18015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJAM.IJAM_73_16

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Creating an efficacious management plan for a patient with an undiagnosed disorder requires vigilance to presenting symptoms while attempting to predict future complications. This requires apt attention by both the clinician and the patient, which is often challenging to achieve. In this final segment of our case report, we present a theoretical treatment approach for our 26-year-old patient with an undiagnosed systemic disorder. Under the premise that, he is afflicted with some sort of connective tissue disease, we formulate a management plan targeting the best prophylactic measures for each of his symptoms. Only with a definitive diagnosis, however, will we be able to best focus our efforts to offsetting his disease progression.
The following core competencies are addressed in this article: Patient care, Medical knowledge.

Keywords: Prevention, prophylaxis, screening, undiagnosed condition

How to cite this article:
Stone LE, Fegley MW, Duarte-Chavez R, Nanda S. Part 4: Clinical management of an undiagnosed systemic condition. Int J Acad Med 2017;3:151-5

How to cite this URL:
Stone LE, Fegley MW, Duarte-Chavez R, Nanda S. Part 4: Clinical management of an undiagnosed systemic condition. Int J Acad Med [serial online] 2017 [cited 2022 Oct 2];3:151-5. Available from: https://www.ijam-web.org/text.asp?2017/3/1/151/209860

  Introduction Top

Correct clinical diagnoses are pivotal for framing an effective approach to clinical management. A known disease has a defined natural history - Progression, clinical manifestations, complications, and effective therapies. Knowing these predictable factors makes prophylactic and therapeutic treatments, follow-up, and prevention of complications more effective. However, when faced with an undefined clinical condition, the luxury of predictability is absent. Instead, we must draw from our knowledge of similar conditions to best serve the patient.

  Case Report Top

The patient is a 26-year-old male presenting to the clinic with systemic complaints. His medical history indicates a vertebral artery aneurysm at age 14 as well as a splenic artery aneurysm, celiac axis aneurysm, and splenectomy at age 21. He has sustained numerous pneumothoraces and demonstrations of reduced gastrointestinal (GI) integrity, including two Mallory–Weiss tears at age 22, Dieulafoy's lesion (DL), and multiple intestinal bleeds. In addition, the patient has multiple café au lait macules (CALMs) on his skin, a high arched palate, and a marked pectus excavatum. Genetic testing revealed non-mutated collagen I and III, fibrillin I, and transforming growth factor-beta (TGF-beta) receptors 1 and 2 genes associated with Ehlers-Danlos Vascular Type, Marfan syndrome, and Loeys-Dietz syndrome, respectively. No definitive diagnosis of his condition has been identified.

  Discussion Top

Despite hopes that our patient's symptoms are sourced from a single pathogenesis, we as clinicians are nonetheless presented with the challenge of how to manage his symptoms in the meantime. Naturally, without a diagnosis, no definitive treatment for his disease is possible. However, we can proactively seek to limit future damage from the processes acting in his system. We approach this last part of our case report as a discussion for effective clinical management of our patient's systemic symptoms, bearing in mind the likelihood of a causative connective tissue pathogenesis (see parts 1, 2, and 3 of this series). Using the symptoms discussed in part 3, we have devised the following categorical structure for our analysis: lung conditions, arterial conditions, GI complications, congenital structural abnormalities, and CALMs. An overview of the discussed topics is shown in [Table 1] and [Figure 1].[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12]
Table 1: Patient's conditions and recommended treatment

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Figure 1: Patient's symptoms categorized by system and need for treatment

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General approach to connective tissue disease management

While we retain hope that our patient will someday be properly diagnosed, we in the meantime must approach his condition with our best differential diagnosis theory – connective tissue disease (see part 3 of this series). If we use connective tissue disease management protocols as a standard of care of our patient, we find the following trends:[1] treatment is a lifelong process of screening high-risk organ systems,[2] surgical interventions are frequent,[3] medications are often indicated. These trends are perhaps disheartening, as they parallel our current, piecemeal approach to this patient's care. However, due to the efficacy of this approach in patients with predictable connective tissue diseases, these core pillars of management nevertheless remain foundational for our patient's treatment plan. We can therefore use therapeutic management protocols for typical connective tissue diseases in order to maximize our patient's chances at an unencumbered life.[13]


Lung conditions

The sudden appearance of lung cysts and subsequent recurrent pneumothoraces is an area of concern for our patient. While pneumothoraces have a number of etiologies, it is likely that his many lung cysts are correlated, if not causative of these recurrences. Current standard of care distinguishes between inpatient and outpatient management, based on etiology and severity. Because our patient exhibits signs of additional lung disease overlying his pneumothoraces (cysts), chest drain, aspiration, and/or inpatient observation are indicated, depending on the severity of the patient's concurrent symptoms.[3]

Furthermore, due to this patient's relapsing course, there are several lifestyle prophylactic measures we can recommend. First, until it is thoroughly established that the lung damage is healed or that the patient has sufficient parenchymal resilience, he must avoid rapid changes in pressure – namely flying and deep water diving. Second, because the current literature finds a statistical significance between cigarette smoke and recurrent pneumothorax, our patient is strongly advised to avoid smoking.[1]

In addition to these softer lifestyle adjustments, patients with cyst-related pneumothorax have seen a reduction in symptoms with video-assisted thoracic surgery (VATS) for bleb minimization. This procedure reduces lung bleb size, decreasing the likelihood of rupture and subsequent tearing of the parenchyma. With this approach, recurrence rates three years post-operatively are recorded at 5% compared to 50% in controls [2],[14] If this approach is taken for our patient, however, we must consider that his lung cyst manifestation is not yet well controlled. Even with a successful VATS, the recurrence of lung cysts will continue to add pneumothorax risk. Therefore, the best prophylaxis we can offer is supervised medical observation, in particular watching for changes in his lung cyst presentation performed by routine computed tomography (CT).

Arterial conditions

Our patient's numerous sporadic aneurysms present an important area of focus in our clinical management plan. Current abdominal aneurysm screening protocols issued by the United States Preventative Service Task Force are unlikely to be useful for our patient as they focus on age as the greatest risk factor for disease.[15] Similarly, the strongest indications for intracranial aneurysm screening are a family history and kidney disease, variables irrelevant in this case.[16] We therefore again turn to connective tissue disease protocols, beginning with screening tests to measure a baseline diameter for high risk arteries. This screening would be repeated 6 months later to detect changes with yearly follow-ups. If the arterial dilation appears to be expanding quickly, then more frequent screenings will be necessary.[4] These initial screenings can avoid radiation – a particular consideration in the young – through the use of transthoracic echocardiography, although subsequent arterial dilation might require cardiac magnetic resonance.[17]

On measures of prophylaxis, patients with connective tissue disease have reported positive outcomes when treated with beta-blockers. While the mechanism is unknown, beta-blockers can help reduce aneurysm dilatation, particularly of the aorta, showing efficacy in all age ranges, especially for Marfan-related aneurysms.[4],[18] Patients with contraindications for beta-blockers can also be placed on calcium channel blockers or antimicrobials such as doxycycline and azithromycin, although the current literature provides less support for this form of treatment. Angiotensin-converting enzyme inhibitors can also be used, with one study suggesting that this treatment might actually decrease aneurysm dilation more than beta-blockers. While the body of evidence to support this assertion is minimal, it presents another option for clinicians when juggling multiple contraindications.[19],[20]

While this medical management approach is geared towards preventing symptoms, increasing focus is being placed on interfacing with the upstream, aberrant pathways likely causative in the aneurysmal etiology. In particular, some success has been demonstrated with angiotensin II Type I receptor blockers, which are hypothesized to correct abnormal TGF-beta signaling commonly seen in connective tissue disease (see part 2 of this series).[5] This approach demonstrates a shift in connective tissue disease treatment that, if efficacious, may better hone the pathophysiological imbalances to yield a more parsimonious treatment plan.

Concerning prophylactic surgical management- clinicians must balance the perceived risk of an unoperated aneurysm with the known risk of surgery. Certain aneurysms have strong evidence supporting surgical intervention. For instance, total splenic embolization is considered an effective means of staving off the risk of splenic rupture. Additional endovascular procedures have shown promise, although evidence for the efficacy of these treatments in connective tissue disease patients is scant.[21],[22],[23] Algorithmic decision-making for invasive procedures in similar patients is also lacking.[20]

Additional prophylactic measures require attentive lifestyle changes by our patient. While encouraged to stay active, contact sports, and isometric exercises should be strictly avoided due to their impact on blood pressure.[4] Regular cardiovascular exercise is a better option, although carefully monitored. In addition, our patient should avoid smoking to prevent unnecessary arterial stiffness from precipitating a rupture.[6]

Congenital structural conditions

High arched palate and pectus excavatum are not typically immediate threats to a patient's well being. Treatment is only indicated if the condition interferes with normal functioning, worsens, or if the patient elects for cosmetic surgery. In the case of high arched palate, more severe forms can be associated with speech difficulties, gingival swelling, and teeth crowding.[24] In addition, patients are at greater risk of (1) obstructive sleep apnea due to maxillo-mandibular insufficiency and (2) complicated intubations.[8] While surgical treatment can be performed to alleviate these latter two situations, the intervention must take place before facial bone ossification completes in the teen years.[25] In severely affected patients, we can recommend speech therapy and encourage careful evaluation, and follow-up by a dentist qualified to treat patients with this condition. For our patient, symptoms are minor abnormalities and do not require additional therapy.

Treatment of pectus excavatum also presents on a spectrum. More severe cases may impinge on thoracic organs. One study reports 95% of patients experiencing cardiac compression while others document significant reductions in cardiopulmonary function.[26],[27] Most importantly, pectus excavatum tends to worsen with time, subsequently increasing such organ dysfunction.[28] Typically, surgery is indicated if the patient presents with a lateral to anterior-posterior sternal ratio of >3.2. Close CT monitoring and attention to the patient's personal preferences are necessary when deciding whether or not to progress to surgical options.[29] The standard of treatment in this domain has improved significantly within the last decade, with the advent of minimally invasive processes demonstrating a 3.7% failure rate and high patient satisfaction.[7]

Gastrointestinal complications

Our patient's GI complaints pose challenges to a medical team because there is little consensus on proper management or treatment. DLs are not usually identified until after a rupture, and very little is known about their etiology, making prophylaxis challenging (see part 3 of this series). For our patient, we can recommend frequent endoscopic screenings – the primary means of DL diagnosis with a 70%–100% diagnostic yield. It should be noted, however, that no consensus has been reached for how frequently these screenings should occur.[9] Once the lesions have been identified, injections of epinephrine, thermal coagulation, endoscopic band ligation, or hemostatic clipping can provide definitive treatment, although efficacy between these treatments has not been rigorously explored.[9] Despite this, because no link has been made between connective tissue and DLs, we are unaware whether or not our patient is considered high risk for future recurrences.

The observed spontaneous GI tears present difficult choices for our patient. If he indeed does have some form of an undiagnosed connective tissue disorder, surgical treatment options become complicated. There is currently no consensus on surgical management for these patients, although some suggest removing the areas of bowel most prone to tearing.[11] However, to pinpoint the area of weakness, patients must have considerable, recurrent, patterned perforations to a degree which has not yet occured in our patient. A case-by-case approach to each perforation is therefore the most appropriate approach, with surgery only being indicated for the most severe occurrences. More conservative management during less severe episodes includes complete bowel rest, suctioning, antibiotics, blood transfusions, and total parenteral nutrition.[10],[30]

Café au lait macules

Due to our extended discussion of CALMs in Part 1 of this series, we find it only necessary to highlight here that CALMs are not in themselves life-threatening. However, they do provide us with clues that some underlying disease process is taking place, especially given the number of macules present on our patient's body. If our patient desired cosmetic removal of these macules, we could suggest laser treatment, although the incidence of recurrence or even macule darkening have been reported.[12] It would instead be our recommendation to not address the CALMs with definitive treatment, but instead to watch whether more appear throughout our patient's lifetime.

  Conclusion Top

Without a definitive diagnosis for our patient, we can only approach treatment with a symptom-by-symptom approach with an overarching suspicion of connective tissue pathogenesis. Our primary goal is to prevent further distress to his system through prophylactic measures such as screening, lifestyle, and medicinal treatment, although the efficacy of these approaches varies by symptom. It is our hope that a diagnosis will bring improved treatment options for this patient and better help predict future manifestations of his disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1]


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