The distribution of cerebral cavernous malformations (CCMs) follows the volume of the neuraxis, such that 80% are supratentorial, 15% are infratentorial, and 3%-5% are within the spinal cord (1,2). Cranial nerve CCMs constitute a distinctly rare subset, accounting for no more than 1% (3-10). The optic chiasm is most frequently affected (4,7,8) but the prechiasmatic optic nerve extremely rarely (11).
We report a young woman presenting with left optic neuropathy that mimicked optic neuritis, but in whom neuroimaging showed multiple cerebral CCMs with familial features.
One week after an 8-month period of breastfeeding her second son, a 30-year-old woman awoke with visual impairment of the left eye. A diagnosis of optic neuritis was made elsewhere. When vision did not improve after 4 retrobulbar corticosteroid injections, she was admitted to our institution for an evaluation.
Our examination disclosed a visual acuity of 20/20 in the right eye and 20/200 in the left eye. There was a left afferent pupillary defect. Ophthalmoscopy showed no abnormalities in the right eye and optic disc edema in the left eye (Fig. 1A). Visual field testing showed no abnormalities in the right eye and blind spot enlargement in the left eye.
Orbital ultrasound showed only elevation of the left optic nerve head. Fluorescein angiography showed no leakage (Fig. 1B). Visual evoked potentials showed no abnormalities upon stimulating the right eye, and increased latency and a reduced P100 amplitude upon stimulating the left eye.
These findings were considered suspicious for left optic neuritis. However, brain and orbit MRI (Fig. 2) showed 2 lesions consistent with CCMs, 1 type III in the left temporal lobe and 1 type II in the right frontal lobe (12), as well as thickening and abnormal signal intensity of the deep intraorbital and intracanalicular portions of the left optic nerve The optic nerve lesion was considered consistent with a type I CCM. CT did not show calcification in any of the lesions.
Treatment included a 3-day intravenous bolus of prednisone (1 g/day), followed by a month of oral administration of prednisolone (50 mg/day), which was then gradually tapered. This treatment resulted in slow improvement in visual acuity of the left eye.
The patient had 2 children, 1 aged 7 years and 1 aged 9 months, as well as a sister aged 25 years, all of whom were apparently healthy. The patient's father, aged 57 years, had purple-black, round, raised, nontender, angioma-like cutaneous lesions in his right leg noted from birth. With age, these lesions had increased in size and easily bled if traumatized. Biopsy of a right leg lesion showed cavernous hemangioma and MRI (Fig. 3) showed multiple type III and IV CCMs (12) in the brain. Genetic analysis of the proband and her father showed a novel pathogenic G235R mutation in the KRIT1 gene (13). The genetic test results were negative in the proband's sister.
A repeat MRI of the proband 4 months later showed reduction in size and signal intensity of the left optic nerve lesion. Four months later, ophthalmologic examination disclosed further improvement of visual acuity in the affected eye to 20/25 with reduction in blind spot enlargement.
However, 5 months later visual acuity in the left eye had regressed to 20/40, and ophthalmoscopy showed increased left optic disc swelling and visual fields showed enlargement of the blind spot. MRI (Fig. 4A) disclosed more left optic nerve thickening and abnormal signal intensity.
Oral administration of acetazolamide (250 mg/day) and some days later oral administration of prednisolone (50 mg/day) for 1 month with subsequent tapering resulted in complete visual recovery. Yet 5 months later, the visual acuity of the left eye regressed again, this time to finger counting. MRI (Fig. 4B) did not show acute or subacute changes. Treatment included a 3-day intravenous bolus of prednisone (1 g/day) and oral administration of acetazolamide (250 mg/day), followed by oral administration of 50 mg/day prednisolone for 1 month with subsequent tapering. However, 1 month after treatment had been started, visual acuity had declined to hand movements in the left eye.
MRI (Fig. 4C) now showed an increase in the size and signal of the intraorbital left optic nerve CCM. Seven months later, visual acuity was no light perception in the left eye. At this stage, MRI showed regression of the optic nerve CCM. Eight and 20 months later, MRIs were unchanged.
We have described a patient who had sudden visual loss in 1 eye with optic disc elevation but no fluorescein leakage that mimicked optic neuritis but proved to be a presumed CCM in conjunction with multiple cerebral CCMs. No intervention occurred, and over several months of fluctuations, visual function was eventually extinguished in that eye.
For CCMs in any location in the neuraxis, MRI is the method of choice for diagnosis, classification, and follow-up (1,2,12). T2* MRI provides the definitive evaluation of the total number of CCMs because of the susceptibility artifacts from microscopic deposits of hemosiderin in chronic phases of hemorrhage. On the other hand, the combination of T1 and T2 images is best to show the acute and subacute hemorrhages. A major limitation of T2* images is the severe signal loss induced by macroscopic field inhomogeneity and diamagnetic susceptibility artifacts at interfaces, which are more common at the skull base. Type I CCMs appear homogeneously hyperintense on T1 images due to methemoglobin predominance in subacute hemorrhage. Type II CCMs are heterogeneous on both T1 and T2 sequences, showing a reticulated mixed signal core (“popcorn”). Type III CCMs are hypointense to isointense on T1 images, hypointense on T2 images, and markedly hypointense on T2* images due to hemosiderin predominance. Type IV CCMs show tiny, punctate foci that are hypointense on T1 and T2 images, often multiple, and best seen on T2* images (2,12). Type IV CCMs rarely enhance, simulating capillary telangiectasias (14,15). None of these 4 MRI appearances is immune from changes into another MRI appearance, and the evolution is not predictable on the basis of the original morphology (1,15,16).
Several authors have noted that patients with type I and type II CCMs are more commonly symptomatic compared with patients who have type III and type IV CCMs (12,16-18). This seems consistent with the history of our patient, but other authors did not find any significant correlation between symptoms and serial MRI changes (15). Perilesional edema and mass effect may correlate with the patient's clinical manifestations.
Although our patient was originally believed to have optic neuritis, the MRI signal characteristics of the lesion were not consistent with that diagnosis. In optic neuritis, the optic nerve shows abnormal signal intensity including low or normal signal intensity on T1 images, high signal intensity on T2 images, and enhancement (19,20). The optic nerve is swollen in the acute phase and may undergo atrophy in the chronic phase (21). In the acute phase, optic neuritis may also present with optic nerve sheath dilatation, probably due to interruption of the communication between the subarachnoid space of the diseased optic nerve and the chiasmal cistern. Optic nerve sheath enhancement suggests meningeal inflammation, as observed in pathologic studies (22).
The MRI findings were also not consistent with a tumor of the optic nerve or optic nerve sheath (23-28), including hemangioblastoma, a benign vascular tumor commonly associated with von Hippel-Lindau disease. Most hemangioblastomas that occur within the orbit are located in the retina, although locations within the optic nerve have been reported. Hemangioblastomas generally show an enhancing portion (23-26).
Cerebral CCMs, which account for 5%-20% of all cerebral vascular malformations, are reported in 0.3% of large autopsy studies, and 0.4%-0.9% of large prospective cohort studies of the general population. Most (50%-80%) CCMs are apparently sporadic. A single CCM may be found in roughly 70% of patients with sporadic CCMs and in 8%-19% of patients with familial disease. Multiple CCMs, indicative of familial forms (1,2,12,13,18,29), are genetically heterogeneous, exhibiting an autosomal dominant inheritance with different preliminary estimates of disease penetrance at 3 loci: KRIT1/CCM1, CCM2, and PDCD10/CCM3, mapped to 7q, 7p, and 3q, respectively. These loci account for approximately 40%, 20%, and 40% of non-Hispanic familial cases, respectively.
Familial CCMs have been shown to have a 0.2%-0.4% incidence per patient per year of de novo lesion formation (1,2,12,18). For this phenomenon, 2 possible developmental mechanisms have been postulated: a Knudson 2-hit mechanism and a haploinsufficiency mode (30-33). De novo formation has been associated with previous irradiation, viruses, hormonal influences in pregnancy, endothelial proliferation, and angiogenesis (2,34-36). Notably, CCMs have the capacity for endothelial proliferation and neoangiogenesis, which may also explain the development of new CCMs along a biopsy tract (35). A small amount of cavernous tissue transplanted to any point along the biopsy tract may induce the transformation of normal capillaries or the growth of new, fragile vessels or recanalization by nearby parenchymal vessels (36).
In the patient reported here, the visual loss started 8 days after the end of breast-feeding. Some authors suggested that pregnancy is a risk factor for growth of intraorbital tumors (37), hemorrhage from cerebral vascular malformations (38) or CCMs (17,39-43), or onset of CCM-related seizures (44), resulting in an aggressive clinical course, especially in the first trimester of pregnancy. However, another series (45) did not find an increase in the risk of CCM hemorrhage in pregnant women, and the paucity of cases in the literature would argue against this hypothesis. Although the biologic effects on CCMs of hormonal and hemodynamic alterations experienced during pregnancy are unknown, in the patient reported here they might have represented a “second hit” to genetically predisposed tissue.
Symptoms of CCMs are thought to result from recurrent episodes of hemorrhage and CCM growth. However, these changes need not cause clinical manifestations. Hemorrhage is characteristically confined within the lesion and may not result in neurologic deficits unless it creates a mass effect. Asymptomatic episodes of small hemorrhage may thus occur (46). On the other hand, clinical deterioration may also occur without any evidence of lesion change on MRI (47). This phenomenon seems consistent with the fact that in anterior visual pathway CCMs, the rise and fall of visual acuity is not necessarily associated with neuroimaging documentation of recurrent tissue hemorrhage (48), as exemplified by our patient.
Surgery may be indicated in symptomatic and accessible CCMs in noneloquent parenchyma. Symptomatic patients with inaccessible lesions are usually observed, despite the often poor natural history. The role of stereotactic radiosurgery in the treatment of CCMs is still debated (2,4). In our patient, the involvement of the proximal intraorbital and intracanalicular segments of the optic nerve precluded surgery or irradiation.
We thank Roberto Faleri from the Central Library, School of Medicine, University of Siena, Policlinico “Santa Maria alle Scotte,” Siena, Italy, for providing important references for the preparation of this scientific article and Tiziana Caselli from the Unit of Neuroimaging and Neurointervention, Department of Neurosciences, Azienda Ospedaliera Universitaria Senese, “Santa Maria alle Scotte” General Hospital, Siena, Italy, for her technical help in preparing the figures.
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