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Clinical case: Raynaud’s syndrome
In this article we describe a case of refractive primary Raynaud's syndrome resistant to standard first-line therapy. You have probably heard about this condition, but do you truly know its sign and symptoms, pathophysiology, and diagnosis? Continue reading to find out more about Raynaud's phenomenon, its anatomy, and possible treatments.
| Raynaud's Disease | It is a condition in which some of the body’s blood vessels (typically those in the fingers and toes) constrict in an exaggerated way in response to cold or emotional stress. It can be primary (idiopathic) or secondary (autoimmune). |
| Cervicothoracic (Stellate) ganglion | It is the main relay station for the sympathetic nerve fibers traveling to the upper limb. It can be ablated or destroyed chemically for therapeutic purposes in the management of Raynaud's syndrome. |
| Treatments for Raynaud's syndrome |
First-line: lifestyle modifications, calcium channel blockers Alternatives: phosphodiesterase type 5 inhibitors, endothelin antagonists, prostaglandin derivatives |
After reviewing this case you should be able to describe the following:
- Raynaud’s phenomenon and the difference between primary and secondary Raynaud’s phenomenon.
- The anatomical pathway that provides the sympathetic innervation to the upper limb. How this pathway facilitates an anatomically based treatment for Raynaud’s phenomenon.
- Sildenafil is frequently used to treat a common condition; why did the physicians prescribe this pharmacological agent in this case?
This article is based on a case report published in the Journal "Case Reports in Surgery" in 2015, by Caroline C. Jadlowiec, Beata E. Lobel, Namita Akolkar, Michael D. Bourque, Thomas J. Devers, and David W. McFadden.
- Case description
- Medical and anatomical considerations
- Explanations to objectives
- Objectives
- Sources
Case description
History
The patient is a 55-year-old female who was diagnosed with primary Raynaud’s phenomenon (PRP) in 2009. PRP initially displayed as a typical bilateral discoloration of the fingers varying among pallor, bluish, and reddish, accompanied by mild pain and numbness (Figure 1).
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The patient did not complain of joint pain, swelling, or deformity and did not show skin rashes, oral ulcers, or dysphagia. The patient’s signs and symptoms were exacerbated by cold weather and stress. She is a lifelong nonsmoker. The patient was initially treated with aspirin, nifedipine, and prednisolone at a different health facility, but no notable improvement occurred.
Physical exam
At the first exam, she did not show any features of connective tissue disease and the physical examination was remarkable because of the bilateral cyanosis of the fingertips, with a left middle finger ulcer (Figure 2A); the lower limb examination showed bluish discoloration over the distal phalanges of right and left second and third toes. Distal pulse and motor and sensory evaluations were normal.
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Laboratory investigations and imaging
Laboratory blood examination for autoimmune analysis and serology, and malignancy screening were unremarkable. The patient’s condition worsened and she was admitted to the hospital with severe digital pain and ulceration. Magnetic resonance angiogram of her upper extremities did not reveal any features of vasculitis, aneurysm, or stenosis.
CT scanning of the aortic arch did not reveal any vascular abnormality. CT angiogram, however, did demonstrate attenuated, irregular right and left ulnar arteries. The patient then underwent bilateral selective ulnar angiography and distal angioplasty, the former of which indicated distal disease at the level of the palmar arches (Figure 3). Biopsy of the left little finger failed to show any significant histopathological abnormalities and was negative for vasculitis.
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Treatment and evolution
Prednisolone therapy was discontinued, and the patient was given a trial of sildenafil (12.5 mg) twice a day. But this agent too failed to halt disease progression and the patient suffered from severe digital pain and bilateral ulceration of the tips of her fingers. Due to persistent symptoms unrelieved by conventional drug regimens, rituximab therapy was initiated and a significant improvement in the patient’s signs and symptoms was noted.
This treatment was continued and after six months the patient showed a complete resolution of the digital ischemia (Figure 2B). However, five years later, the patient experienced a recurrence of her previous symptoms (Figure 2C) which were resolved by a second cycle of rituximab (375 mg/m2 weekly for four weeks; Figure 2D). Currently, the patient is in complete remission.
Medical and anatomical considerations
The Raynaud phenomenon (RP) is a condition in which some of the body’s blood vessels (typically those in the fingers and toes) constrict in an exaggerated way in response to cold or emotional stress. The normal control of how blood vessels respond to cold and other stimuli is complex, involving the central nervous system, peripheral sensory nerves, and receptors within the blood vessels.
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RP occurs when this complex and delicate system of control is abnormal. Classically the condition is attributed to hyperactivation of the sympathetic nervous system causing extreme vasoconstriction of the peripheral blood vessels, leading to tissue hypoxia. As shown by the current case, RP likely has a much more complex etiology than simply sympathetic system hyperactivation.
A RP episode can be triggered by exposure to cold temperature or by a shift in temperature from warm to cool. Thus, even mildly cold exposure, such as that caused by air conditioning or the cold of the refrigerated food section in a grocery store, can cause a RP attack. A general body chill can also trigger an attack, even if the hands and feet are kept warm. Emotional stress and being startled can cause an attack of RP due to the release of neurotransmitters that affect the muscular layer within the arteries.
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The present case demonstrates the successful use of rituximab in a patient with PRP that was resistant to alternative, therapeutic management options; however, it remains unclear whether autoantibodies have a substantive role in the pathogenesis of primary or secondary RP (see Explanation 1 to Objectives). Previous studies have established the presence of antibodies against type IV collagen in patients with PRP, which may explain the response to rituximab in the present case. Rituximab is an antibody against cell surface protein CD20, which is expressed on B cells. Rituximab may induce the killing of B cells by complement-dependent cytotoxicity (CDC) or by antibody-dependent cellular cytotoxicity (ADCC), which activates natural killer cells. Further studies are required to establish the role and efficacy of this novel treatment in PRP and secondary RP.
Explanations to objectives
Objectives
- Raynaud’s phenomenon and the difference between primary and secondary Raynaud’s phenomenon.
- The anatomical pathway that provides the sympathetic innervation to the upper limb. How this pathway facilitates an anatomically based treatment for Raynaud’s syndrome.
- Sildenafil is frequently used to treat a common condition; why did the physicians prescribe this pharmacological agent in this case?
Raynaud's phenomenon
RP is divisible into primary Raynaud’s phenomenon (PRP) and secondary Raynaud’s phenomenon (SRP) according to the underlying etiology. Primary Raynaud’s phenomenon (PRP) refers to vasospastic episodes of peripheral arterioles in the fingers and toes that are characterized by triphasic color changes associated with physical, chemical, or emotional triggers and with pain and/or numbness. It is generally a benign condition with an unknown etiology and a prevalence of about 5% in the general population.
Secondary Raynaud phenomenon (SRP) is the term used when Raynaud’s is associated with another medical condition or disease, often of a rheumatic nature, such as scleroderma, lupus (systemic lupus erythematosus) and rheumatoid arthritis. Often, RP is the first sign that the patient has an underlying connective tissue disease. Patients with SRP are more likely than those with PRP to suffer serious conditions such as skin ulcers (which can cause serious long-term damage to the blood vessels), or even gangrene. Transition to SRP from PRP is not uncommon and expression of late onset disease, abnormal nailfold capillaries, positive antinuclear antibody (ANA), or other autoantibodies and digital ischemia or ulceration may predict it (some of these symptoms were prevalent in the patient described in our case).
Nonpharmacologic lifestyle modifications and calcium channel blockers (e..g, nifedipine in this case) are the first-line treatment for RP. Other drugs, including phosphodiesterase type 5 inhibitors, endothelin antagonists (bosentan), and prostaglandin derivatives may be used in severe cases. In the case described here, conventional treatments were not successful and rituximab proved effective. This suggests that the patient might have some underlying autoimmune condition.
Sympathetic innervation of the upper limb
The sympathetic outflow exits the spinal cord with the anterior rami of spinal nerves T1-L2. The preganglionic fibers that are destined to innervate the blood vessels of the upper limb exit the spinal cord with the anterior rami of the upper thoracic spinal nerves and reach the sympathetic trunk where they ascend. Most of the fibers exit the trunk at the level of the cervicothoracic ganglion and synapse within this ganglion (figure 4). The postganglionic fibers then join with the branches of the brachial plexus to reach the arteries and sweat glands in the upper limb.
The cervicothoracic ganglion (figure 5), which is not a distinct structure in about 30% of individuals, represents the combined C8 and T1 paravertebral ganglia. It is generally oval in shape and measures 2.5 cm long, 1 cm wide and 0.5 cm thick and is usually located posterior to the subclavian artery and anterior to the first rib. The cervicothoracic ganglion lies lateral and posterior to the lateral edge of the longus colli muscle. Although most of the sympathetic fibers to the upper limb pass through this ganglion, some fibers pass through the intercostobrachial nerve (anterior ramus of spinal nerve T2) and thus bypass the cervicothoracic ganglion.
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A cervicothoracic ganglion block involves the infiltration of local anesthetic to prevent the conduction of nerve impulses through the ganglion. This block is often used for diagnostic purposes, but also may have temporally therapeutic value. A more permanent anatomical treatment of Raynaud’s disease is ablation of the ganglion, now typically done using radiofrequency ablation. Chemical destruction of the ganglion has also been done. Complications that have been observed from a cervicothoracic ganglion block include Horner's syndrome, intra-arterial or intravenous injection, difficulty swallowing, vocal cord paralysis, epidural spread of local anesthetic and pneumothorax.
Sildenafil In the management of Raynaud's syndrome
Sildenafil (Viagra) is a selective inhibitor of cGMP-specific phosphodiesterase type 5. Its most common usage is for erectile dysfunction. However, besides its role in this condition, sildenafil provides general cGMP-dependent microvascular and macrovascular dilation. Thus, sildenafil has been successfully used in non-erectile dysfunction conditions such as primary and secondary pulmonary hypertension, and also has been shown to be effective in RP.
Clinical case: Raynaud’s syndrome: want to learn more about it?
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