Intracranial Hypertension due to Sigmoid Sinus Thrombosis
The six year old boy described in this case, whose clinical symptoms included only headache without papilledema or focal neurological signs, had isolated intracranial hypertension documented by increased opening pressure at lumbar puncture. Substantial clinical improvement in symptoms was observed following the lumbar puncture, as is frequently observed in cases of intracranial hypertension. However, the age and gender of the patient are somewhat atypical in many series of patients with idiopathic intracranial hypertension (pseudotumor cerebri), and the rapid onset of symptoms (over a few days) also raised a concern that the elevated CSF pressure might be secondary to an identifiable cause.
MRI and MRV imaging showed evidence of thrombosis of the sigmoid sinus on one side, with normal drainage of the remaining venous system, and no evidence of venous infarction. No evidence of systemic vascular occlusions was evident on the history and general examination.
The earliest description of cerebral vein and dural sinus thrombosis is attributed to Ribes in 1825. The true incidence of this disorder is unknown, as many cases are asymptomatic or difficult to distinguish from benign symptoms. However, evidence of cerebral vein or sinus thrombosis was documented in 9% of 182 consecutive autopsies, with a 2:1 female preponderance. Furthermore, sinovenous thrombosis was diagnosed in 3.75 percent of a pediatric population undergoing angiography. These data suggest that the incidence of cerebral sinovenous thrombosis, at least in selected populations of patients, may be underestimated in the published literature.
Cerebral veins have thin walls with minimal smooth muscle, no valves and no vasomotor innervation. The cerebral venous vasculature consists of a superficial sinovenous system (dural venous sinuses) and a deep venous system. Venous territories are less well defined due to the presence of collateral circulation. In the majority of cases, cerebral venous thrombosis (CVT) involves multiple dural sinuses or both sinuses and veins. Rather than a rapid occlusion of the vessel, which appears to be usual for arterial occlusions, CVT should be considered as a continuing process in which the balance of prothrombotic and thrombolytic processes is disturbed, leading to progression of the venous thrombus over a longer period of time. CVT causing venous infarction is frequently hemorrhagic, with bleeding in the brain parenchyma, subarachnoid or subdural spaces. The predisposition to hemorrhage is believed to result from elevated venous and capillary pressure caused by persistent thrombosis. Venous infarcts may occur, which do not conform to an arterial territory. Because of the increased venous pressure, there is early swelling of the infarct and adjacent brain. The cerebral venous sinuses most frequently thrombosed are the superior sagittal sinus (72%) and the lateral sinuses (70%). In about one-third of cases, more than one sinus is affected, which correlates with a poorer prognosis. In a further 30-40% of cases, both sinuses and cerebral or cerebellar veins are involved, also correlating with a poorer prognosis.
The clinical presentation is amazingly variable. Four main patterns have emerged. The first and most common pattern exhibits focal signs such as focal deficits or seizures with a focal onset. These focal deficits, which depend upon the location and territory of the veins involved, include aphasia, hemiplegia, hemisensory disturbance, cortical sensory loss, hemianopia, thalamic dementia, choreoathetosis and akathisia, monoplegia of the contralateral leg (from superior cerebral vein involvement), Rolandic vein involvement causing spastic weakness of the proximal upper and lower extremity (sparing face and speech), vein of Galen thrombosis causing hemorrhagic infarction of the medial basal ganglia and thalami with resultant movement disorders. Due to the midline location of most sinuses, focal abnormalities are frequently bilateral and affect the legs more than the arms. Prominent fluctuation of focal neurological signs is also seen. Seizures occur in 30-50% of cases, often with focal onset, and often followed by a Todd's paresis.
A second pattern suggestive of CVT is that of isolated intracranial hypertension with presentations of headache, papilledema and sixth nerve palsy. Headache presentation can be varied, mimicking subarachnoid bleed, thunderclap headache, migraine with and without aura, and sharp monocular headaches. Isolated intracranial hypertension may be the only sign of cerebral venous thrombosis as reported recently. Biousse et al. reported 59 of 160 (37%) of patients with CVT presented with isolated ICH. Leker et al. reported 12 of 46 (26%) of patients with CVT met the diagnostic criteria for PTC (pseudotumour cerebri). In both of these studies, conventional angiography or MRI & MRV confirmed the presence of CVT. Both groups suggested that even patients meeting the classic criteria for diagnosis of pseudotumor cerebri should be evaluated with MRI/MRV or conventional angiography to rule out CVT. In this view, pseudotumor cerebri should be considered a diagnosis of true exclusion.
A third presentation of CVT, less commonly encountered, is that of subacute encephalopathy characterized by a depressed level of consciousness without localizing signs or recognizable features of raised intracranial pressure. A fourth presentation of CVT provides a distinctive picture due to painful ocular symptoms and cranial nerve palsies from cavernous sinus thrombosis. A Korsakoff-like amnestic syndrome with confabulation has been described with bilateral mesial temporal lobe infarction following bilateral cavernous sinus thrombosis. Furthermore, thrombosis of the cavernous sinus may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) from effects on the nearby pituitary. The differential diagnosis of cavernous sinus thrombosis includes dysthyroid ophthalmopathy, orbital cellulitis, superior orbital or orbital apex syndromes and Tolosa-Hunt syndrome.
In neonates and infants, seizures are the most prominent symptom, presenting as early as one hour after birth. Lethargy, irritability and a bulging fontanelle, dilated scalp veins, scalp veins, Greisinger's sign (edema over the site of the mastoid emissary vein), Crowe's sign (when the lateral sinus is occluded, compression of the contralateral jugular vein may lead to distention of the scalp and face veins), hydrocephalus, macrocephaly, opisthotonus, developmental delay, and hemorrhage into the thalami or ventricles may occur in neonatal CVT. The "sunset" sign, resulting from tonic downward deviation of the eyes, is a clue to the presence of increased intracranial pressure in the neonate.
Concomitant venous thrombosis may occur in other organ systems (calf veins, pelvic veins, hepatic veins, and/or extracranial veins. Pulmonary emboli associated with CVT may result from embolization from the cerebral sinuses, from concurrent leg vein thrombosis, or from a generalized thrombophilia if the patient is predisposed. The prevention of pulmonary embolism is probably an important ancillary benefit of anticoagulation in patients with CVT, particularly patients with an identified predisposition to thrombus formation.
Predisposing factors can be identified in 65-80% of patients with CVT. Therefore, all apparently idiopathic cases, as is the case with this patient, should be followed with repeated investigations before a final diagnosis of idiopathic CVT is rendered. The principal diagnostic distinction should be made between infective and non-infective causes of CVT. There has been a dramatic decline since the introduction of antibiotics in the relative incidence of septic intracranial venous sinus disease, which now constitutes only 8-10% of all cases.
Particular infectious factors predisposing to CVT in children include ear infection (acute and chronic otitis media and mastoiditis), peritonsillar abscess, complications of encephalitis and bacterial meningitis, and orbital or periorbital infections (due to retrograde flow from facial and orbital veins into the cavernous sinus). Among non-infectious factors predisposing to CVT in children are included cyanotic heart disease, leukemic infiltrates of cerebral veins, perinatal asphyxia, neuroblastoma or primitive neuroectodermal tumors encroaching upon, or metastatic to, cerebral sinuses, skull abnormalities (osteopetrosis, achondroplasia, craniometaphyseal dysplasia) which constrict venous outflow, and the Sturge-Weber syndrome. In the Sturge-Weber syndrome, there is frequently evidence of impaired superficial cortical venous drainage beneath the leptomeningeal angiomatosis, and enlargement or tortuosity of deep venous collaterals. Whether the cortical veins are thrombosed or atretic in this disorder is unclear. Data suggesting that aspirin therapy may prevent neurologic deterioration in Sturge—Weber patients supports this hypothesis.
The differential diagnosis in this particular case report, especially with involvement of lateral sinuses, includes "otogenic hydrocephalus," or intracranial hypertension resulting from septic lateral sinus thrombosis associated with an ear infection. This term is a misnomer, since the ventricles are usually not dilated in this condition. Septic lateral sinus thrombosis was once a common complication of acute otitis media and mastoiditis in children, but now is more often associated with chronic ear infections and petrous cholesteatomas in adults. High fever, weight loss, earache, headache, photophobia, ear discharge, and positive Crowe's and Greisinger's signs suggest this diagnosis. Focal neurologic deficits are rare in lateral sinus thrombosis without the development of an intracranial abscess or spread into other sinuses or cortical veins. Brain abscesses arising from the temporal lobe or cerebellum, extradural abscess, and palsies of lower cranial nerves may complicate septic lateral sinus thrombosis. Cranial nerve deficits may include glossopharyngeal, vagus and accessory nerve palsies arising from involvement of the jugular bulb, hypoglossal nerve palsies from involvement of the vein of the hypoglossal canal, and abducens nerve palsies from involvement of the inferior petrosal sinus. Non-septic lateral sinus thrombosis is more commonly reported than septic thrombosis. Lack of fever, absence of peripheral leukocytosis, a normal ESR, and MRI showing only minimal mucosal thickening in the sinuses and minimal changes in the mastoid, as well as a clinical response to conservative therapy, suggest a non-septic cause of thrombosis in this case. A minimal degree of mucosal irregularity within mastoid air cells, as was noted in this patient on MR imaging, may be associated with nonseptic causes of lateral sinus thrombosis. It is particularly important to avoid attributing undue importance to minimal MRI changes in the absence of fever or clinical signs suggestive of otitis media or mastoiditis.
Potential Causes | Examples |
|---|---|
Septic thrombosis | Bacterial (including syphilis), fungal, viral (HIV, CMV, lymphoma) and parasitic (trichinella) |
Trauma | Penetrating and nonpenetrating head injuries, iopamidol myelography |
Hematologic | Polycythemia vera, sickle cell anemia, cryofibrinogenemia, paroxysmal nocturnal hemoglobinuria, thrombocytosis, thrombocytopenia or heparin-induced thrombocytopenia (HIT), disseminated intravascular coagulation (DIC), severe anemia, lymphoma |
Coagulopathies | Antithrombin III deficiency, protein C and S deficiency, factor V mutation, antiphospholipid antibody syndromes, DIC, matenal twin transfusion |
Neoplasia | Metastatic disease; lymphoma; primitive neuroectodermal tumors |
Inflammatory | Behcet's disease (20-25% of Arabic patients with CVT), Wegener's granulomatosis, Cogan's syndrome, Kohlmeier-Degos syndrome, systemic lupus erythematosus, polyarteritis nodosa, sarcoidosis, Crohn's disease |
Hemodynamic states | Dehydration, fever, cardiac decompensation |
Hormonal | Pregnancy and puerperium (particularly in first few weeks postpartum), thyrotoxicosis |
Vascular disorders | A-V malformations, arterial occlusions |
Medications | Androgens, oral contraceptives, progestogens, L-asparaginase, epsilon-aminocarproic acid, "ecstasy" and similar drugs of abuse) |
There appears to be interaction between inherited and environmental risk factors as reported by Martinelli et al. In this study, for patients with CVT, the odds ratio for carriers of the factor V and prothrombin gene mutations were 10.2 and 7.8, respectively, while that for oral contraceptive use was 22.1. In carriers of the prothrombin gene mutation who were also contraceptive users, the odds ratio jumped to 149.3. Screening of asymptomatic women initiating oral contraceptives is not needed. However, screening for these factors after even a single episode of venous thrombosis in patients on oral contraceptives is reasonable.
Blood counts, erythrocyte sedimentation rate (ESR), and if clinically indicated, blood cultures to rule out infection are important in all patients suspected of having CVT. Lumbar puncture may reveal normal CSF or increased pressure, but observation of red cells, elevated protein or xanthochromia increases the likelihood that venous infarction or hemorrhage has occurred. CSF cultures are usually sterile, even in septic venous thrombosis. Ophthalmological evaluation and visual field-testing are important, especially if visual symptoms occur. A thorough evaluation for clinically relevant causes of CVT should be performed, and apparently "idiopathic" cases should be followed over time, and possibly re-evaluated, before a final diagnosis is rendered.
Neuroimaging is critically important in cases of intracranial hypertension or suspected CVT. CT imaging may be needed in the emergency setting to exclude acute hemorrhage or mass effect. Intravenous contrast increases the sensitivity, but not necessarily the specificity. The "empty delta sign" is seen only in one-third of patients with CVT, usually 3-4 days after the ictus and persisting for 2-3 months. The differential diagnosis of an empty delta sign include early splitting of the sinus (normal variant), delayed delta sign in normal delayed postcontrast scans, extradural hypodensity such as an abscess abutting the sinus, and subarachnoid blood outlining the superior sagittal sinus on precontrast studies. Other findings suggestive of CVT on enhanced CT studies include dilated transcerebral medullary veins, tentorial and falcine enhancement, and asymmetric meningeal enhancement over the cavernous sinus (note that the latter is difficult to appreciate on routine CT images without specific attention to this region).
MRI offers numerous advantages over CT, due to its ability to visualize the thrombus itself as an increased signal on T1 and T2 images, as well as the ability to show parenchymal disease with better definition. With MR imaging, there are fewer false negatives than with CT, except at a very early stage (before day 5) when the thrombosed sinus can still be hypointense or just isointense and when there is substantial slowing of blood flow.
When MRI is equivocal, angiography is indicated. MRI in combination with MRV (magnetic resonance venography), two-dimensional and three-dimensional time-of-flight and phase contrast, has generally replaced dye angiography for screening. In isolated cortical vein thrombosis, invasive angiography may still be necessary when indirect signs such as dilated corkscrew collateral veins occur in a poorly vascularized area. Retrograde filling of the superior ophthalmic vein and delayed venous drainage may be nonspecific signs of increased intracranial pressure, and do not necessarily indicate a venous occlusion. Filling defects produced by mixed contrast and unopacified blood from the opposite hemisphere may be avoided by aortic arch injections or intravenous digital angiography as the contrast bolus reaches both hemispheres simultaneously.
Helical cerebral CT venography is promising to become an excellent imaging modality for CT-based imaging systems, with greater ease of use in the acute setting. Transcranial Doppler has limited utility, but can be used to detect microembolic signals in the internal jugular vein.
Factors associated with a poor prognosis are fast rate of thrombus evolution, age of patients (high mortality rate in infancy and in the aged), an infectious cause, the presence of focal symptoms and coma, presence of an hemorrhagic infarct on CT scans, involvement of cerebellar veins and thrombosis of the deep cerebral veins. Among the favorable associations is cerebral sinovenous thrombosis associated with the postpartum state.
If the patient survives the initial event, recovery is much better than from an arterial stroke (Lausanne Stroke Registry), and only 15% of patients are left with disabling sequelae. The long-term outcome of CVT is less well understood. In patients with lateral sinus thrombosis, arteriovenous malformations have been reported as late sequelae. Recurrence of CVT is infrequent. Preter et al. reported only 12% recurrence in a series of 77 patients followed for a mean of 78 months. Recurrences have been mostly reported in hospitalized -patients, or in patients with an underlying prothrombotic condition. Most authors recommend using oral anticoagulation for 3-6 months at which time they should be reevaluated with MRI/MRV. Prolonged anticoagulation may be required for refractory cases or for patients with an identified prothrombotic state. For peripartum CVT, the risk of recurrence during a later pregnancy is poorly defined but seems low. At the time of publication, there were no recurrences in 16 pregnancies followed by Preter et al. Residual epilepsy has been reported in 10-30% of patients who had seizures during the acute stage. Seizures usually occur in the first year and are easily controlled with antiepileptic drugs.
Medical management of CVT should include attention to the treatment of seizures, broad-spectnun antibiotics for septic thrombosis, detection and management of metabolic derangements, and management of cerebral edema and elevated intracranial pressure. Other medical management may be dictated by the clinical situation. Treatment for specific causes of CVT varies, but may include high dose steroids and other immune suppressants in Behcet's disease or vasculitides, and wide spectrum antibiotics in septic CVT.
Anticoagulants: The primary rationale for anticoagulation in sinovenous thrombosis is to prevent further thrombus formation and thereby prevent the development of venous infarction, both bland and hemorrhagic. However, in patients with hemorrhagic venous infarction, anticoagulation may cause further intracerebral bleeding. Evidence has been accumulating in favor of heparin in large retrospective and prospective series in terms of better prognosis in patients treated with heparin and low risk of intracerebral bleeding even in patients with a hemorrhagic brain lesion.
Einhaupl et al., in the first prospective randomised, placebo-controlled study of 20 patients with CVT, showed a significant difference in favor of intravenous heparin with a target aPTT of 80-100 seconds. The trial was stopped after 20 patients because of this dramatic difference: eight patients in the heparin group but only one in the placebo group recovered fully. The presence of hemorrhage within a venous infarction was found before the onset of anticoagulation in three patients randomized to heparin, and did not preclude clinical recovery. No hemorrhages occurred after starting heparin. Two patients receiving placebo had evidence of hemorrhage at the time of randomization, and an additional three patients in this group subsequently developed intracranial bleeding. The authors also retrospectively analyzed 102 patients with CVT, and suggested that intravenous heparin was even beneficial in those patients who had evidence of hemorrhagic transformation prior to starting heparin. This study did not report on the extent of sinus involvement, and the low number of patients enrolled is a further weakness.
De Bruijn et al., in a placebo-controlled trial of 60 patients, tested low molecular weight heparin (three weeks) followed by warfarin (10 weeks). The primary outcome measures of death or a Barthel Index less than 15 after three weeks occurred in 20% of low molecular weight heparin patients and 24% in the placebo group. This difference was not statistically significant but suggested a trend toward favorable outcome in treated patients. In comparison to the previous findings, this study also suggested that anticoagulation was safe, even in patients with evidence of hemorrhagic venous infarction. However, this study also suggested a lower mortality (10%) than had been previously thought to be associated with CVT, as well as the possibility of a full recovery without any antithrombotic treatment. Fifty patients in this study (88%) had involvement of the superior sagittal sinus, 14 of whom also had involvement of the straight sinus. Overall, the straight sinus was thrombosed in 17 cases (29%).
Anticoagulants are often employed in cavernous sinus thrombosis to prevent thrombosis of the intracavernous carotid artery, septic embolism or extension of thrombus to contiguous dural sinuses. Anticoagulants may be used for lateral sinus thrombosis to treat systemic embolic phenomena but are otherwise not generally recommended. Syms et al., in their report on septic lateral sinus thrombosis, do not consider heparinization necessary except for prophylaxis of deep venous thrombosis, or with thrombus propagation after surgery. However, others (e.g., Rosen & Scher) are more aggressive in recommending anticoagulation. Clearly, more work is needed to determine whether groups of patients with a predicted lower risk of poor outcome would also benefit from anticoagulation.
Most investigators believe that children and adolescents with CVT do not behave differently from adults. Generally, patients with extensive sinus or multiple vein involvement, parenchymal involvement (including minor hemorrhage suggestive of venous infarction, but excluding extensive hemorrhage), and patients with evidence for an underlying thrombophilia should be anticoagulated. However, the possibility of full recovery without any antithrombotic treatment is argued in the De Bruijn study. Thus, anticoagulation in patients with an isolated sinus thrombosis, particularly in the lateral sinuses, who lack other clinical signs or laboratory evidence suggesting a poor outcome or a high risk of extension or recurrence, is a reasonable treatment option, but cannot be generally recommended on the basis of the available data. Thrombolysis is a tantalizing alternative to heparin (Horowitz et al., Frey et al., Kim et al.), but its role remains unconfirmed. Given the evidence supporting the efficacy of heparin, thrombolytic therapy should probably be reserved for those patients who rapidly decline despite adequate anticoagulation. The most frequent cause of worsening, however, is inadequate anticoagulation. Surgery in patients with septic lateral sinus thrombosis involves removal of perisinus infection and needle aspiration of the sinus. Other radical procedures depending on the severity include end to end saphenous vein bypass and jugular vein ligation. Surgical thrombectomy for aseptic lateral sinus thrombosis and superior sagittal sinus thrombosis may be considered in patients with a rapidly progressive course despite appropriate medical therapy. Surgery is not recommended for cavernous sinus thrombosis unless it is intended to remove a source of infection. Decompression of the optic nerve may be considered if visual function deteriorates.
Otitis and mastoid infection were deemed unlikely in view of the relatively normal white blood count, sedimentation rate, and CSF studies, together with the absence of historical or clinical evidence suggesting infection, and only minimal changes in the mastoid air cells on MRI. An intensive search for a hematologic predisposition to thrombus formation has so far been unrevealing. After a full discussion of various treatment concerns, this patient was managed conservatively with intravenous hydration, and was not anticoagulated. He was discharged on the third day with good control of his headache symptoms. He had a normal ophthalmologic evaluation. The patient failed to follow up in clinic but was reportedly doing well when contacted by telephone four months after discharge. However, we have not yet documented recanalization on a subsequent MRI/MRV, and this patient will be followed closely for some time and elements of his evaluation repeated before receiving a final diagnosis of idiopathic CVT.
This case report is particularly important to highlight the growing evidence that "pseudotumour cerebri" should be a diagnosis of exclusion, as isolated intracranial hypertension can be the only sign of cerebral venous thrombosis. Although we elected in this case to manage the patient with conservative treatment, this was only after defining an isolated thrombosis on MRI/MRV studies, and extensive screening for factors which would predispose to poorer outcome or recurrence. As pointed out recently by Leker and Steiner (2000), dural sinus thrombosis may not always have a good outcome even when presenting initially as "benign" intracranial hypertension.
Email comments: