Cerebral Venous Thrombosis Following High-Dose Corticosteroid Therapy in a Patient With Relapsing Multiple Sclerosis

November 1, 2007

A 35-year-old right-handed white man presented with an 8-day history of left leg weakness and difficulty in walking. A day after the onset of symptoms, he self-medicated with oral prednisolone for 1 day and tapered the medication over 6 days. The leg weakness improved over the course of treatment but worsened afterward. His medical history is significant for multiple sclerosis (MS) and restless legs syndrome. He had 1 previous exacerbation of MS 3 years ago.

Figure 1. Cranial MRI scan(FLAIR) showing periventricularhyperintense lesions compatiblewith multiple sclerosis plaques.

Figure 2. Cranial magnetic resonancevenogram demonstratingocclusion of the left transverseand sigmoid sinuses.

HISTORY AND PHYSICAL EXAMINATION

A 35-year-old right-handed white man presented with an 8-day history of left leg weakness and difficulty in walking. A day after the onset of symptoms, he self-medicated with oral prednisolone for 1 day and tapered the medication over 6 days. The leg weakness improved over the course of treatment but worsened afterward. His medical history is significant for multiple sclerosis (MS) and restless legs syndrome. He had 1 previous exacerbation of MS 3 years ago. His past medical and surgical history is otherwise unremarkable, and he reported no recent illness, trauma, or travel. He has no allergies and is up-to-date on immunizations. Medications include glatiramer acetate (Copaxone) and pramipexole (Mirapex). The patient smokes about half a pack of cigarettes per day. Family history and review of systems are noncontributory.

On presentation, mental status, funduscopic, and cranial nerve examinations were normal. Motor examination of the arms and right leg was normal. Strength of the left iliopsoas was 3/5, quadriceps 5/5, hamstrings 4/5, and distally 5/5. Gait was mildly slow with a left circumductive pattern. Reflexes were diffusely hyperactive, with negative Babinski reflexes bilaterally. Remaining aspects of the examination, including sensation and cerebellar function, were normal.

Because of the history and neurological examination, an MS exacerbation was strongly suspected. The patient was given a 7-day tapering course of intravenous methylprednisolone.

IMAGING STUDIES

A brain MRI with and without contrast at 1.5 T was performed the day following completion of the course of methylprednisolone. There were innumerable T2 hyperintense lesions of the bilateral hemispheric white matter with involvement most confluent periventricularly (Figure 1). Many lesions demonstrated diminished T1 signal and increased signal on diffusion-weighted images. On postcontrast images, however, there was no evidence of intraparenchymal enhancement. When clinically correlated, these imaging findings were consistent with an MS exacerbation.

There also was a lack of enhancement within the distal aspect of the left transverse sinus, left sigmoid sinus, and the origin of the left jugular vein. The findings were highly suggestive of cerebral venous sinus thrombosis (CVT), but there was no evidence of arterial or venous infarct.

A follow-up brain magnetic resonance venogram (MRV) at 1.5 T a few days later showed no flow-related enhancement within the left transverse and sigmoid sinuses, strongly suggestive of CVT (Figure 2). A magnetic resonance arteriogram of the cerebral arteries was normal. At the time of the MRI and MRV, the patient reported no new neurological symptoms-specifically denying headache-and improvement in the left leg weakness.

LABORATORY TESTS

The patient was evaluated with a coagulation workup, which was normal for protein C, protein S, antithrombin III, factor V Leiden, lupus anticoagulant screening, and anticardiolipin antibody testing. Liver function tests were normal, as were prothrombin time/partial thromboplastin time and international normalized ratio (INR) levels. Basic metabolic panel values, complete blood count, erythrocyte sedimentation rate, Lyme titer, and rapid plasma reagin were within normal limits.

CVT is an unusual and enigmatic condition because of its protean and sometimes nonspecific manifestations. The predisposing factors and causes to consider are numerous, and the clinical course is highly variable.1,2 Surprisingly, in some cases the condition is completely asymptomatic and is only detected at autopsy.2 Although CVT could coexist with other neurological conditions, there is a paucity of literature on its association with MS or corticosteroid treatment.

The finding of CVT in this case was rather intriguing because it did not present with any of the usual symptoms.1 There was no history of headache, papilledema, seizures, altered level of consciousness, focal neurological deficits, or meningeal signs. Asymptomatic CVT is a well-recognized entity. What makes this case unusual, however, is that our investigation did not reveal features compatible with any of the common causes that are observed in approximately 25% to 35% of cases.1,2 The only other plausible predisposing factors were the patient's recent MS exacerbation and corticosteroid use.

Anecdotal reports have correlated high-dose corticosteroid treatment in MS patients with an increased risk for developing CVT.3-5 All reported cases had received high-dose methylprednisolone for the first time following lumbar puncture and other predisposing factors for CVT were excluded, except for a history of oral contraceptive use and smoking in 2 patients.

A recent study by Stolz and colleagues6 showed that acute CVT developed in 5% of a cohort of 120 patients during intravenous corticosteroid treatment for relapse of a definite MS. Strikingly, this rate is as high as that expected in protein C or S deficiency.7 A potentiation of the corticosteroid effect by acquired and inherited risk factors is plausible; Stolz and colleagues6 found an incidence of 30% for coagulopathies in their patient cohort. More than 50% of patients had one or more acquired risk factors, which is significant in this case because our patient is a smoker.

Despite this information, a conclusive cause-effect relationship between corticosteroids and CVT has not been established. Corticosteroids are used to treat disease that themselves predispose to CVT.3

Our patient's MS is less likely to be responsible for the development of CVT. Except for the possible link with corticosteroid therapy or use of other thrombotic agents, no increased risk of venous thrombosis in association with MS has been reported. Eight patients with MS and CVT have been reported.8-11 One patient was a bedridden patient with end-stage MS, 3 were taking oral contraceptives at the time of thrombosis, and 3 received corticosteroids or lumbar puncture at the time of CVT. Four of the patients received a thrombophilia workup (all normal) and 3 did not. Only 1 patient with concurrent MS exacerbation and CVT had no recent corticosteroid treatment or risk factors.

TREATMENT GUIDELINES

To our knowledge, there are no evidence-based guidelines or consensus for the treatment of asymptomatic/ incidental CVT found during or after corticosteroid treatment for MS exacerbation. In some of the aforementioned case reports, asymptomatic patients received no specific treatment for their CVT but were provided with prophylactic anticoagulant treatment.8,10

THE CASE: COURSE AND OUTCOME

After the MVR confirmed the likely presence of a CVT, the patient was given warfarin. The MS exacerbation responded well to intravenous corticosteroids. At 1-month follow-up, the patient has a normal neurological examination and denies any symptoms. He continues to take glatiramer acetate and a prophylactic anticoagulant (warfarin) for his asymptomatic CVT, with a target INR of 2.5.

IN SUMMARY

CVT remains an uncommon entity, but it is extremely important for clinicians to recognize it clinically and radiographically. This case suggests that high-dose corticosteroid therapy for MS exacerbation may be associated with a risk of venous thrombosis when other risk factors are present and that prophylactic anticoagulant treatment may be warranted. Severe headaches, seizures, or new focal neurological deficits in such patients should lead to the exclusion of a diagnosis of acute CVT.

References:

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