Clinical manifestations

Presentation and course

The clinical manifestations of a carotid-cavernous fistula can be predicted by the structures within the cavernous sinus that are affected by the fistula. Therefore, a carotid-cavernous fistula may present with palsies of cranial nerves III, IV, V1, V2, or VI. In addition, anterograde venous flow may cause orbital and ocular venous congestion, resulting in proptosis, chemosis, arterialized venous loops on the sclera, increased intraocular pressure with subsequent glaucomatous vision loss, and engorgement of the extraocular muscles resulting in further restriction of eye movement.

Direct fistulas present dramatically due to the large volume of blood that is being shunted.

Although fistula occurs most commonly on the side of head trauma, it may rarely occur on the contralateral side (28). In a series of 98 consecutive patients presenting with direct fistulas, the most common symptom was a prominent orbital bruit (80%), followed by proptosis (72%), and chemosis (55%). Isolated ipsilateral abducens palsy occurred in 49%, retro-orbital pain or headaches in 24%, ophthalmoplegia in 23%, and vision loss in 17% (52).

Intracranial hemorrhage may develop in 5% of patients with direct carotid-cavernous fistula. About 2% of these types of intracranial hemorrhages can present with life-threatening nosebleeds (94).

A rare presentation of direct fistula is brainstem venous congestion, resulting in reduced consciousness, facial numbness, dysarthria, and gait ataxia (13). Unilateral limb weakness was observed in a patient with contralateral basal ganglia congestion (30).

By contrast, indirect (“dural”) carotid-cavernous fistulas present more insidiously due to the smaller volume of shunted blood. These patients are typically middle-aged or elderly women.

Indirect carotid-cavernous fistulas, draining posteriorly into the petrosal sinuses, lack proptosis or the orbital bruit. The absence of conjunctival congestion gives the indirect carotid-cavernous fistula the moniker “white-eyed shunt” (01). These fistulas are often asymptomatic. Another presentation is sudden, isolated ocular motor nerve palsy almost always associated with ocular or orbital pain. The third nerve is the most often involved cranial nerve and can be complete with pupil involvement, incomplete with pupil involvement, or incomplete with pupil sparing. Cerebral angiography can distinguish it from a cerebral aneurysm or microvascular palsy.

In contrast, anterior-draining indirect fistulas usually produce orbital congestion and visual symptoms resembling direct carotid-cavernous fistulas. This manifests as conjunctival congestion, proptosis, chemosis, ocular motor paresis, and orbital pain. Close inspection reveals the characteristic radial pattern of arterialization that distinguishes it from chronic conjunctivitis.

Increased intraocular pressure, retinal vessel occlusion, ischemic optic neuropathy, or proliferative retinopathy lead to tractional retinal detachment and vision loss in 30% of patients (63). Increased intraocular pressure can also follow angle closure from massive choroidal effusion (91). However, anteriorly draining indirect carotid-cavernous fistulas may present without ocular or orbital signs. One patient presented only with headache and isolated abducens nerve palsy. The anastomosis between the superior ophthalmic vein and angular facial vein prevented pressure buildup and the typical ocular or orbital signs (41).

Another distinguishing feature of indirect carotid-cavernous fistula is the waxing and waning nature with spontaneous improvement or closure in up to 60% of patients (82). Spontaneous closure may occur even in those with florid clinical symptoms such as optic neuropathy and orbital congestion (12). Thrombosis of the fistula may contribute to this improvement. Recurrence or change in clinical symptoms may occur if the thrombus dissolves or migrates.

A retrospective study of 47 patients with cavernous-carotid fistulas (26 indirect, 21 direct) revealed a similar presentation of both groups with headache and ocular manifestations like proptosis, conjunctival injection, ophthalmoparesis, chemosis, and visual acuity loss. Direct fistulas occurred more often in younger patients compared to indirect fistulas (48 vs. 62 years). Vision loss on presentation was three times more likely to result in residual symptoms, independent of the classification (32).

Prognosis and complications

The overall prognosis of a carotid-cavernous is fistula good, with over 80% experiencing complete cure after endovascular treatment (27). The main cause of death with indirect carotid-cavernous fistulas is intracerebral hemorrhage, which occurs at a rate of approximately 1.8% per year (21). Up to 60% of indirect carotid-cavernous fistulas will close spontaneously or after diagnostic angiography alone, thus, obviating the need for intervention (82; 14). Close observation of indirect carotid-cavernous fistula for as long as the ocular symptoms remain mild and there are no neurologic symptoms is reasonable. Elevated intraocular pressure that occurs in indirect fistulas may respond to medical management alone. In one series of 14 eyes, nine had elevated intraocular pressure of which only three had unfavorable intraocular pressure control. Only one of these eyes required glaucoma surgery (42). Differential diagnosis of vision loss includes irreversible ischemic optic neuropathy, proliferative retinopathy, and choroidal detachment and effusion (36). If the patient develops uncontrollably high intraocular pressure, intractable exposure keratopathy from proptosis, unacceptable diplopia, or intracerebral hemorrhage, the fistula should be closed.

Direct fistulas have higher morbidity and mortality compared to indirect fistulas. Out of 127 patients with direct fistulas, 3.9% died, whereas no one died from indirect fistulas. Additionally, the rates of intracerebral or subarachnoid hemorrhage (3.1% vs. 0%), life-threatening epistaxis (3.1% vs. 0%), and increased intracranial pressure (8.7% vs. 3.6%) were much higher for direct versus indirect carotid-cavernous fistulas. Subarachnoid hemorrhage from a direct carotid-cavernous fistula portends a particularly grim prognosis, with all four of these patients dying quickly (34).

Clinical vignette

History. A 47-year-old man was hit by a car several months before evaluation. Since the accident, he had developed swelling and redness in the left eye. The eye hurt when exposed to light.

Physical examination. The physical examination showed visual acuity of 20/40 bilaterally. He had gross proptosis and periorbital swelling of the left eye, and a thrill was present over the left eye. The intraocular pressure was 8 mm Hg in the right eye and 16 mm Hg in the left eye.

Diagnostic tests (angiography). A catheter angiogram revealed a direct carotid-cavernous sinus fistula located at the left proximal posterior genu and cavernous sinus. There was significant dilatation of the superior ophthalmic vein. There was so much shunting that there was little to no filling in the left hemispheric arteries. This was diagnosed as a type A carotid-cavernous sinus fistula.

Treatment. The fistula was treated with a microcatheter guided up the internal carotid artery and through the rent in the carotid to the superior ophthalmic vein. Multiple coils were placed in the superior ophthalmic vein. As the coils filled the superior ophthalmic vein, shunting decreased and the arteries of the left hemisphere became visible. Once the ophthalmic vein was coiled, a stent was placed in the internal carotid artery over the rent to prevent coils from falling back into the parent vessel. Additional coils were then placed to occlude the cavernous sinus.

Outcome. The patient’s pain proptosis and chemosis significantly improved after the procedure. He had no restriction of extraocular movements, and the diplopia resolved.

Biological basis

Etiology and pathogenesis

Direct carotid-cavernous fistulas are usually associated with head trauma, surgery, or endovascular intervention. Other reported causes include stent-assisted coil embolization of an intracavernous carotid aneurysm, mechanical thrombectomy for stroke, and craniofacial surgery (14; 02; 102).

Most direct carotid-cavernous fistula are posttraumatic. These fistulas may result from bone fractures tearing the intracavernous internal carotid artery from its dural attachment or from shearing of this vessel due to inertia (77). In absence of bone fractures, increased intraluminal pressure resulting from abrupt compression of the carotid arteries (eg, during sudden neck flexion) has been suggested as a potential mechanism. Rupture of the vessel occurred most often in the C4 segment of the internal carotid artery. Because the C4 segment is free of the trabeculae of the cavernous sinus, Parkinson “tearing” hypothesis cannot completely account for fistula formation (38). With increased utilization of endovascular thrombectomy for acute stroke treatment, microcatheter deployment may perforate the internal carotid artery (66).

Development of the direct carotid-cavernous fistulas may be facilitated by weakening of the arterial wall due to an aneurysm, Ehlers-Danlos syndrome (65), fibromuscular dysplasia (40), pseudoxanthoma elasticum (83), or osteogenesis imperfecta (25).

Indirect fistulas, unlike direct fistulas, are rarely caused by trauma. They usually appear spontaneously and insidiously in middle-aged to elderly women following rupture of the thin-walled dural arteries that normally cross the cavernous sinus (72). Collateral anastomoses may develop after venous thrombosis in the cavernous sinus (92; 84). This may explain why dural fistulas are more common in women especially during pregnancy and the early postpartum period (96). Additionally, a congenital defect is suggested by indirect fistulas in infants without an obvious risk factor (51; 29). Mechanical thrombectomy may also cause indirect fistula (53).

Epidemiology

Direct carotid-cavernous fistulas occur with an incidence ranging from 0.17% to 1.01% after traumatic brain and facial injury (90). In a series of 100 consecutive direct carotid-cavernous fistulas, 76 were caused by trauma, 22 by a ruptured aneurysm, and two were iatrogenic. Motor vehicle accidents and falls were the most common traumatic causes. Most trauma-related cases occurred in young men, whereas aneurysm rupture occurred predominantly in older women (52).

A retrospective chart review of 312 patients showed that in basal skull fractures, the incidence of direct carotid-cavernous fistula is 3.8% and up to 8.3% if the middle cranial fossa is usually involved (54). In another retrospective study, 11.5% of patients developed a direct cavernous carotid fistula within two weeks of treatment of a cavernous aneurysm with a flow diverter (85).

Intracranial dural arteriovenous fistulas account for 10% to 15% of all intracranial arteriovenous malformations (71). Of these, indirect carotid-cavernous fistulas account for approximately 12% and are the second most common type of intracranial dural fistula after those involving the transverse sigmoid sinus. Thus, at most 0.0018% (approximately 5400 people) of the United States population would be expected to have an indirect carotid-cavernous fistula.

Prevention

As most direct carotid-cavernous fistulas occur after trauma, head protection against trauma is reasonable. Iatrogenic related direct fistula can be prevented by thorough knowledge of the patient’s carotid vasculature and medical history. For example, inadvertent creation of a direct fistula during transsphenoidal surgery for pituitary adenoma is more common in patients with a history of previous transsphenoidal surgery or radiation treatment. Preoperative evaluation of intracranial vasculature with magnetic resonance or digital subtraction angiography may prevent creation of a direct carotid-cavernous fistula during tumor resection (50).

Although there is no proven way to reduce the incidence of indirect carotid-cavernous fistulas, treating hypertension, atherosclerosis, and thrombophilia seems sensible.

Differential diagnosis

Because direct carotid-cavernous fistulas typically present with prominent orbital or ocular congestion, the main differential diagnoses include orbital processes such as thyroid eye (Graves) disease, idiopathic orbital inflammation (inflammatory orbital pseudotumor), orbital cellulitis, intraorbital tumor (eg, meningioma), or the various other causes of cavernous sinus syndrome (eg, carotid-cavernous thrombosis or Tolosa-Hunt syndrome). The main distinguishing aspect is the association of direct carotid-cavernous fistulas with recent, severe head trauma.

In contrast, indirect carotid-cavernous fistulas present more insidiously and are confused with benign entities such as conjunctivitis. One distinguishing feature of both direct and indirect carotid-cavernous fistulas is the presence of orbital bruit on auscultation. In almost all cases, the appropriate imaging study will reveal the diagnosis. In absence of imaging, the following pearls can help distinguish carotid-cavernous fistulas from other masqueraders.

Direct carotid-cavernous fistulas.

Thyroid eye disease. Though thyroid eye disease may present with exophthalmos and limitation of ocular movement, it usually does so in a subacute manner and without trauma. Typically, both eyes are involved asymmetrically, with characteristic retraction of the upper eyelid. Chemosis and conjunctival injection are less common and not as prominent compared to direct carotid-cavernous fistulas (11).

Idiopathic orbital inflammation. This entity encompasses all nonspecific orbital inflammation that cannot be attributed to infection, tumor, or another identifiable cause. Signs and symptoms depend on the orbital structures involved, ranging from a mild myositis to a severe orbital apex syndrome. It also may present acutely, subacutely, or chronically and, thus, may mimic both direct and indirect carotid-cavernous fistulas. Like a direct carotid-cavernous fistula, it usually presents unilaterally and can have severe orbital signs as well as severe scleral injection from scleritis. However, in contrast to a direct carotid-cavernous fistula, it is not typically associated with trauma or an orbital bruit. Idiopathic orbital inflammation is also exceptionally sensitive to corticosteroids unlike most of the entities listed in this differential (43).

Orbital cellulitis. This condition presents with severe proptosis, eyelid edema, pain with extraocular eye movements, and vision loss. However, infection occurs over several days and is often preceded by upper respiratory infection, nasal congestion, or sinusitis. Infection is associated with constitutional symptoms such as fever, decreased appetite, or malaise. Cellulitis responds to antibiotics (95).

Intraorbital tumor. Many intraorbital tumors present with proptosis, paralytic or restrictive ocular movements, and vision loss, especially if they involve the orbital apex. The orbital tumors present more insidiously as they typically grow slowly. Corkscrew conjunctival vessels are not found with intraorbital tumors.

Vertebral-venous fistula. A case of vertebral-venous fistula resembling a carotid cavernous fistula was diagnosed by angiography. Although extremely rare, it should be kept in mind if carotid angiography is normal in a patient with symptoms consistent with a carotid cavernous fistula (33).

Indirect (“dural”) carotid-cavernous fistulas. In addition to the above differential diagnoses, indirect carotid-cavernous fistulas initially may be confused with simple ocular inflammation including blepharitis, conjunctivitis, episcleritis, or scleritis. However, indirect carotid-cavernous fistulas are not associated with discharge and will not resolve with topical antibiotics or anti-inflammatory medications. The conjunctival or scleral injection associated with these ocular inflammatory diseases can be discriminated from the typical radial, corkscrew vessels of carotid-cavernous fistulas. Lastly, cranial nerve palsies and other intracranial manifestations (eg, headache or transient ischemic attacks) occur frequently in indirect carotid-cavernous fistulas but not in these ocular inflammatory conditions.

Diagnostic workup

Direct fistulas present with dramatic orbital signs after severe head trauma and often have basal skull fractures. The patients describe a whooshing noise or a heartbeat bruit in their head. The bruit can be auscultated with a stethoscope placed over the eye or at the temple. Arterialization of the conjunctival vessels occurs more frequently in carotid-cavernous fistulas compared to other orbital diseases. Indirect fistulas, especially those draining posteriorly, are more difficult to diagnose by history and physical examination alone. One should still suspect them in any middle-aged to elderly woman presenting with a spontaneous red eye, chemosis, isolated or multiple cranial nerve palsy, and mild orbital congestion (62). Misdiagnosis is common. A retrospective series of 24 patients with carotid cavernous fistula identified two patients misdiagnosed with cluster headache, one as an orbital fracture and one as thyroid eye disease (07).

Ocular pulse amplitude. Another office diagnostic procedure that may help diagnose a carotid-cavernous fistula is measuring the ocular pulse amplitude. The ocular pulse amplitude is the difference between the maximum and minimum intraocular pressure during the cardiac cycle and can be determined by tonometry. One study showed an ocular pulse amplitude of more than 1.6 mmHg to be 100% sensitive and 93% specific in distinguishing carotid-cavernous fistulas from normal subjects or those with other orbital diseases. However, direct and indirect carotid-cavernous fistulas cannot be distinguished from each other by the ocular pulse amplitude (31). The ocular pulse amplitude has been shown to normalize after closure of the fistula by endovascular embolization (31; 47).

CT and MRI based techniques. The radiographic evaluation of a carotid-cavernous fistula will likely begin with noninvasive imaging such as CT, CT angiography, MRI, MR angiography, or transcranial Doppler ultrasound. A CT scan is usually the initial imaging study that is performed in patients with acute head trauma and may heighten the clinician’s suspicion for the presence of a carotid-cavernous fistula. In the case of direct carotid-cavernous fistulas, a CT scan will show proptosis of the involved globe, expansion of the cavernous sinus and superior ophthalmic vein, possible enlargement of the extraocular muscles, and any suspicious skull fractures (82).

Magnetic resonance imaging (MRI) has similar diagnostic utility to CT but is less sensitive in detecting bone fractures. An abnormal cavernous sinus flow void suggests presence of a carotid-cavernous fistula. In one study of indirect carotid-cavernous fistulas, CT detected a dilated superior ophthalmic vein more often than MRI. MRI also found an abnormal flow void in the cavernous sinus in 11 of 12 patients with indirect carotid-cavernous fistulas (98).

CT angiography allows direct visualization of the carotid-cavernous fistula (22). In one study, CT angiography matched the catheter angiography and was superior to MRA in finding and assessing the carotid-cavernous fistulas. This advantage was even greater in diagnosing direct carotid-cavernous fistulas involving the C4 segment of the internal carotid artery (15). A review of 18 consecutive patients with a carotid-cavernous fistulae analyzed the most sensitive and specific imaging features on CTA Early enhancement and dilatation of the superior ophthalmic vein had 100% sensitivity. Arterial-phase contrast in the cavernous sinus had 88.9% sensitivity (09). 4D CT angiography is being increasingly used to diagnose neurovascular problems (99; 59).

MRA also can directly visualize a carotid-cavernous fistula but is less likely to delineate the small arterial feeder vessels or cortical venous drainage routes compared to traditional angiography (86). 4D flow MRI may provide a quantitative analysis of flow velocity and volume using time-resolved phase-contrast MRI for preoperative evaluation of a direct carotid cavernous fistula (69).

Ultrasound. Other noninvasive imaging modalities are transcranial, transorbital color Doppler, and carotid duplex ultrasonography (17; 18). Ultrasound facilitates the diagnosis of indirect fistulas that may be missed by CT or MRI and measure the flow characteristics of both indirect and direct fistulas. Color Doppler ultrasound may indicate the need for invasive conventional angiography, assess the collateral capacity of the circle of Willis, and judge the outcome of the intervention (48). Orbital color Doppler ultrasound (OCDUS) can rule out an anterior-draining carotid-cavernous fistula (100).

Digital subtraction angiography. The gold standard for diagnosis of both direct and indirect carotid-cavernous fistulas is catheter angiography. Cerebral angiography can localize the fistula, delineate the feeder vessels, and assess the drainage pattern. If the cavernous sinus is draining superiorly into the cortical veins, intracerebral hemorrhage and possible hemiparesis may be prevented by emergency treatment. Angiography can map the optimal route of approach, transarterial or transvenous, whether the fistula is being fed bilaterally, and the capacity of the circle of Willis (24). A common regimen that answers these questions includes selective injections of both internal carotid arteries and external carotid arteries, the ipsilateral vertebral artery, the ipsilateral ascending pharyngeal artery, middle and accessory meningeal arteries, and proximal and distal internal maxillary arteries (60). In a retrospective study of only eight patients, using the DSA-Dynavision in treatment planning allowed more precision in their treatment and reduced the time of treatment (10).

Management

The definitive treatment of any arterial-venous fistula is obliteration of the abnormal connection. There are four methods of treatment: conservative, endovascular, stereotactic radiation, and surgical. The type of fistula often determines the treatment of choice but there still is no randomized clinical trial evaluating the optimal approach.

Conservative treatment. Indirect fistulas may close spontaneously or after diagnostic angiography alone in as many 60% of patients (79; 82). The conservative treatment consists of a trial of carotid compression, which promotes thrombosis (39; 35; 45). The affected carotid is occluded with the opposite hand for 10 seconds three times an hour while awake. The occlusion time is gradually increased. After the second day, the patient compresses the artery for 15 seconds three times an hour for 2 days, then 20 seconds three times an hour for 2 days, then 25 seconds three times an hour for 2 days, then 30 seconds three times an hour. This method is less effective with direct fistulas, due to the high flow. Complete resolution of symptoms was reported in 21% to 34% of indirect carotid-cavernous fistula patients (39; 35; 45).

Conservative management alone may be successful even without thrombosis or closure of the indirect fistula. For example, one series found that 82% of patients (39 of 48) recovered or significantly improved with conservative treatment (26). However, a retrograde venous drainage pattern diagnosed by angiography raises the risk of intracerebral hemorrhage and mortality by 30% if the closure is delayed (35).

Endovascular treatment. Endovascular treatment is the primary means of treating carotid-cavernous sinus fistulas. The surgical intervention is reserved for failures. Direct and indirect fistulas can be closed either by transarterial or transvenous routes, or a combination. The endovascular modalities include coils, stents, flow diverters, liquid embolics, particles, carotid sacrifice, detachable balloons, a vascular micro-plug, or combinations of these (08).

Direct fistulas are usually closed by a transarterial coiling. Occasionally, a stent is need to prevent the coil from falling into the parent vessel (67). In a series of 172 patients with direct fistulas, endovascular occlusion rate was 94%, with a 70% rate of preservation of the carotid artery (19). Mortality and morbidity were 0.6% and 2.4%, respectively.

Flow diverters are also used to treat direct fistulas (101; 93; 81). A systematic review showed that flow diverters used alone, or as adjunct treatment may be useful, but long-term data are not available yet (89). Covered stents and flow diverters allow reconstruction of the vessel without occluding the sinus (49; 55; 73).

Indirect fistulas are challenging to treat because of multiple feeding vessels, that are often small, tortuous, and difficult to reach. The transvenous approach via the inferior petrosal sinus is the preferred route. Other options include the superior petrosal sinus, basilar plexus, pterygoid plexus, the facial vein, or even a direct puncture of the dilated superior ophthalmic vein or percutaneous access to the facial vein with ultrasound guidance (64; 60; 61; 104; 70; 23; 103; 57; 03). Coils, liquid embolics, or particles are used for embolization. Robotic surgery has been used to embolize an indirect fistula (46).

In a retrospective analysis of 267 patients, obliteration was accomplished in 86.5% (04). An exclusively transvenous approach had the highest obliteration rate of 86.9%. The transvenous approach using coils only had the highest likelihood of achieving a cure. Coiling alone had a lower complication rate when compared to liquid embolics with or without coiling.

Occasionally, a tortuous carotid artery limits the endovascular access to the fistula. An alternative modality to treat indirect fistulas in patients with contraindications for endovascular approach is endoscopic endonasal orbital apex decompression (87).

A direct fistula can be closed by sacrificing the carotid artery. Safety of the procedure is tested preoperatively by transient carotid artery occlusion. With the patient awake, under continuous clinical observation, the carotid artery is occluded for 15 minutes by balloon inflation. A nuclear perfusion study is performed afterwards. If the clinical and perfusion testing confirm robust collaterals, the artery may be sacrificed safely.

Surgical treatment. Surgical closure of the fistula involves posterior orbitotomy or craniotomy to gain access to the cavernous sinus (78; 82; 68; 88). In a series of 19 patients who failed endovascular treatment, 100% of the carotid-cavernous fistulas were closed with direct surgery. However, three patients (16%) required a graft to bypass the trapped intracavernous carotid artery, and approximately 26% of procedures required sacrifice of the internal carotid artery or a bypass graft (97).

Radiotherapy. Targeted radiotherapy with gamma knife or X-Knife® triggers thrombosis and occlusion of the fistula. The closure rate for 22 indirect fistulas was 90.9%, with no recurrences during follow-up up to 14 years. However, improvement may take on average 2.4 months, and complete occlusion may take 7.5 months (05). This latency is consistent with other similar studies (80; 74; 20).

Complication rates depend on the radiotherapeutic modality. In one study, X-Knife® delivered higher radiation doses to the lens, optic nerve, optic chiasm, and brainstem compared to gamma knife (75). Stereotactic radiotherapy closed only a third of posttraumatic direct fistulas (05). In a retrospective study of 18 cases, at two years, 83% of patients had total obliteration of the direct carotid-cavernous fistula with stereotactic radiosurgery (76).

In patients with ocular compartment syndrome, emergent canthotomy/cantholysis may be performed by the ophthalmologist to decrease the intraocular pressure, as an emergency vision saving procedure (58).

Outcomes

Angiographic occlusion of the fistula predicts good outcome (44). Of 34 patients with both direct and indirect fistula, all showed complete recovery, and only one patient (3%) had a complication. Possible complications of treatment include intracranial hemorrhage or groin hematoma after endovascular treatment, new neurologic deficit, infection, recurrence, or endocrine dysfunction (37). The syndrome of inappropriate antidiuretic hormone secretion after Onyx embolization of bilateral direct carotid-cavernous fistulas was described in one patient (16).

Special considerations

Patients with impaired renal function. Renal dysfunction may aggravate following use of contrast during endovascular treatment. The risks and benefits must be weighed carefully and discussed with the patient and family. Radiotherapy may be an option.

Pregnancy

Women may develop indirect carotid-cavernous fistulas during pregnancy or post-partum due to increased risk of cavernous sinus thrombosis (96). In addition, the hemodynamic changes during pregnancy may explain reopening of a previously resolved direct carotid-cavernous fistula. The backflow to the cortical veins led to intracerebral hemorrhage and hemiplegia (56).