Idiopathic granulomatous angiitis of the CNS manifesting as diffuse white matter disease

Idiopathic granulomatous angiitis of the CNS (IGANS) is a rare condition characterized by small- and medium-sized vessel vasculitis confined to the CNS. The disease presents with severe headache, altered mental function, and focal neurologic deficits; constitutional symptoms of fever, weight loss, anorexia, and vomiting are occasionally present.¹ MRI is more sensitive than CT, but findings are nonspecific and may resemble vascular, neoplastic, and demyelinating disease.^2-4 We describe a patient who presented with MRI features that mimicked a primary white matter disorder resulting in delayed diagnosis.

Case report. A 48-year-old right-handed man was well until 6 months before admission, when he noted bilateral-leg weakness and difficulty walking. Over the next several months he began to walk with a cane, and several weeks before admission he required the use of a walker. His family, social, and medical history was unremarkable; general physical examination was also unremarkable. Neurologic examination demonstrated mental status, cranial nerves, sensory modalities, and cerebellar functions to be normal. Deep tendon reflexes were 3+ throughout, and plantar response was bilaterally extensor. Bilateral ankle clonus and spasticity of the lower extremities were noted. Motor examination demonstrated the upper extremities to be strong. Lower extremities demonstrated 3/5 hip flexor weakness. 4/5 quadriceps weakness, and 3/5 dorsiflexor weakness. Gait examination showed the patient had difficulty getting out of a chair to the standing position and thus was unable to take any steps.

The following laboratory tests were negative or normal: complete blood count, platelet count, electrolytes, liver function tests, blood glucose, angiotensin converting enzyme, BUN and creatinine, urinalysis, HIV, HTLV-I, VDRL, Lyme serology, serum vitamin B₁₂ and folate, 6 A.M. cortisol, arylsulfatase A, and very long-chain fatty acids. The CSF protein level = 98 mg/dL, cell count = 21 lymphocytes, glucose = 75 mg/dL, oligoclonal bands =(absent), total IgG = 9.3 mg/dL (n = 0 to 3.4), IgG index = 0.4 mg/dL (n = 0.3 to 0.7), and sedimentation rate = 30 (n = 0 to 15). Chest radiograph, EEG, and visual evoked response were normal. CT of the head showed decreased attenuation in the centrum semiovale with mass effect and faint central enhancement (figure 1A). MRI of the head showed increased signal on T2-weighted and proton density images in the centrum semiovale with mass effect but without contrast enhancement(figure 1B). MRI of the entire spine was normal.

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Figure 1. (A) CT on admission with decreased attenuation in centrum semiovale. (B) Axial fast spin-echo MRI on admission with increased signal on T2-weighted image (3,550/119/1 [repetition time/echo time/excitations]) bilaterally in centrum semiovale. (C) CT 7 months after admission with complete lesion resolution. (D) MRI 7 months after admission with reduction of white matter involvement on T2-weighted image (3,750/119/1).(E) MRI 10 months after admission with marked progression of white matter involvement on T2-weighted image (3,750/119/1).

Diagnostic brain biopsy was recommended, but the patient refused. A 5-day course of IV methylprednisolone, 1 g per day, was carried out, after which the patient noted improvement in his condition so that he could ambulate a short distance with a walker, which he previously could not do. After 7 months repeat CT demonstrated complete lesion resolution, and MRI showed reduction of area and intensity of white matter involvement(figure 1, C and D). His clinical status had improved to walker-assisted and then quad cane ambulation. At 10 months the patient complained of increased difficulty walking, headache, and backache. CT and MRI (figure 1E) showed extensive white matter involvement, with contrast enhancement on MRI. IV methylprednisolone again resulted in marked clinical improvement. At 11 months severe decompensation occurred, and IV methylprednisolone again resulted in dramatic clinical improvement; CT returned to near normal, whereas MRI was unchanged.

Several similar episodes occurred over the next 1½ years; each responded to a short course of steroid therapy. Approximately 3 years after onset of symptoms, the patient became nonambulatory. An open brain biopsy was performed. The biopsy specimen from the right frontal lobe was a portion of cortex and white matter measuring 2.5 × 1.5 × 1.5 cm showing no gross abnormality. Microscopy showed minimal lymphocytic infiltration of the leptomeninges; the superficial blood vessels were unremarkable. Extensive perivascular lymphocytic infiltrates were seen in the white matter, with some small vessels showing intramural lymphocytes. Vascular necrosis was not a feature, but several small vessels deep in the biopsy specimen showed noncaseating granuloma formation involving the vessel walls(figure 2). The white matter showed no evidence of perivascular demyelination or of macrophage activity. Luxol fast blue stain showed slight diffuse pallor and vacuolation of the white matter, indicative of edema; this stain also accentuated the relatively sparse reactive gemistocytic astrocytes. Perivascular lymphocytes did not show atypia to suggest neoplasia. Immunoperoxidase stains for varicella-zoster virus were negative, and no viral forms were seen with electron microscopy. Electron microscopic (EM) examination did not show specific vascular abnormalities; there was evidence of edema of the white matter, but the myelinated fibers appeared intact.

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Figure 2. Brain biopsy specimen showing perivascular mononuclear infiltrate with involvement of vessel wall with granuloma (arrowhead) (H-E staining, magnification ×160, before 47% reduction).

The patient was started on prednisone 80 mg/d and cyclophosphamide 100 mg/d. After 1 month on this regimen the patient could transfer independently and assist in activities of daily living. No additional improvement was noted, and after 8 weeks prednisone was tapered. At 10 weeks cyclophosphamide was discontinued, and methotrexate 15 mg/week was started. The patient has been on immunosuppressive therapy for the past 4 months with no additional change in neurologic status and is maintained on methotrexate 7 mg/week.

Discussion. The uncharacteristic, myelopathic presentation and MRI manifestations suggestive of white matter disease delayed the diagnosis and treatment of IGANS in our patient. The neurologic, laboratory, and neuroimaging features as well as the clinical response to steroids suggested myelinoclastic diffuse sclerosis, a variant of multiple sclerosis.⁵ Metachromatic leukodystrophy, adrenoleukodystrophy, and the various leukoencephalopathies were excluded by specific laboratory investigations. The need for definitive diagnosis, because of the possibility of atypical primary CNS lymphoma,⁶ and possible treatment with long-term immunosuppressive therapy prompted brain biopsy, which led to the unexpected finding of angiitis.

The vasculitis of IGANS predominantly involves the small- and medium-sized arteries and veins of the leptomeninges and brain parenchyma demonstrating granulomatous, lymphocytic, or necrotizing inflammation, with granulomas present in less than one-half the cases.⁴ Given the focal and segmental nature of the angiitis, open brain biopsy of parenchyma and leptomeninges is recommended because either alone may miss the vasculitic process; a nondiagnostic biopsy occurs in 18% of patients.¹ Before the diagnosis of IGANS, our patient responded to short courses of steroids. Subsequent management with cyclophosphamide and prednisone resulted in limited clinical improvement after 1 month. No additional change occurred after 2 months, and both medications were discontinued and methotrexate was instituted. Despite recovery in the majority of patients treated with immunosuppressive therapy,⁷ only modest improvement occurred in others.⁸ Early diagnosis may affect treatment outcome, as a serial cerebral angiographic study has demonstrated that segmental narrowing with dilatation and stenosis is potentially reversible; however, prolonged inflammation may heal with fibrosis and fixed narrowing after years of disease, supporting discontinuation of immunosuppressive therapy in such case.²

MRI findings of IGANS are commonly focal, may be multiple and bilateral, in both gray and white matter, and are more prominent in the latter and on T2-weighted images. Less commonly, hemorrhage, mass effect, leptomeningeal, parenchymal, cortical ribbon, or punctate enhancement with gadolinium is seen.⁴ White matter changes, largely caused by edema from an impaired blood-brain barrier, frequently resolve with immunosuppressive therapy; however, residual MRI changes often persist. Although MRI features resembling demyelinating disease have been reported with IGANS,² bilateral, diffuse, relatively symmetric white matter changes mimicking leukoencephalopathies and leukodystrophies are limited to several case reports^4,8,9 and occurred late in the course of the disease in association with deep gray matter involvement or distinguishing enhancing characteristics. MRI findings in our patient accompanied the clinical presentation and were confined to the white matter. Cerebral angiography is insensitive and nonspecific,^1,4 with false-negative results occurring in as many as 50% of patients, caused in part by the small caliber of involved blood vessels. In patients with MRI features of diffuse white matter involvement, in whom thorough clinical and laboratory investigations find no cause for the acquired neurologic deficit, brain biopsy should be considered to exclude IGANS.