INDEX

INTRODUCTION

NEUROIMAGING FINDINGS INWEGENER'SGRANULOMATOSIS

DISCUSSION

INTRODUCTION

WG is a systemic disease characterized by the triad of granulomatous lesions of the upperand lower respiratory tract, focal segmental glomerulonephritis, and disseminatednecrotizing vasculitis. Clinical features are detailed in Table 1. Most patients present withsymptoms and signs referable to the upper respiratory tract, and most will have concurrentevidence of lower respiratory tract involvement, sometimes subclinical. This is nowreferred to as initial phase or limited disease. After a median delay of 5 months, thesystemic phase of the disease appears, marked by systemic necrotizing vasculitis,preferentially involving small arterioles, capillaries and post-capillary venules, andcrescenteric glomerulonephritis, with rapid progression to renal failure.

Table 1. CLINICAL FEATURES OF WEGENER'S GRANULOMATOSIS

Male: female ratio 1.2:1Age range (mean)(years) 9-83(41-50)Signs and Symptoms Fever (%) 50

Anorexia and weight loss (%) 35

Sinusitis (%) 61-85

Otitis media 32-42

Eye manifestations (orbital pseudotumor,episcleritis, scleritis, uveitis, retinitis [%])

41-52

Cough (%) 20-28

Pleuritis (%) 67

Nodules/infiltrates on chest radiograph 11-30

Hemoptysis (%) 45

Skin lesions (palpable purpura, papules,vesicles, ulcers, nodules

67

Arthralgias/arthritis (%) 29

Neurologic manifestations 15

Peripheral nervous system 8

Central nervous system (%) 39-45

System Involvement

Respiratory tract

o Upper (%) 90

o Lower (%) 48-85

Renal (%) 77

Eye (%) 39-52

Neurologic involvement (Table 2) may occur in any phase of the disease, and particularneurologic features reflect the particular pathologic process involved: direct invasion ofparanasal and para-aural tissues by the granulomatous process, "metastasis" of thegranulomatous process to sites within the CNS that are not contiguous with the upperairways, and necrotizing vasculitis. Direct invasion of the orbit and temporal bone appearsto account for orbital pseudotumor with associated involvement of extraocular muscles, theoptic and oculomotor nerves, and deafness caused by labyrinthine involvement-as well asdestruction of the seventh and eighth cranial nerves; however, most cranial nerve palsies,as well as pituitary damage, appear to reflect granulomatous basilar meningitis, reflecting"metastatic disease" that is not contiguous with disease of the upper airways. Thispachymeningitis can extend well up over the cerebral convexity or along the falx ortentorium and can account for "cerebritis" associated with seizures and focal neurologicdeficits. (1) It may also involve the spinal canal, producing myelopathy. Vasculitis offers thebest explanation for peripheral neuropathy, which, like the neuropathy of PAN, ischaracteristically a mononeuritis multiplex. Vasculitis also offers a plausible explanation ofischemic stroke and intracerebral and subarachnoid hemorrhage (rare), and has beenpathologically demonstrated in a number of cases.

Table 2. NEUROLOGIC MANIFESTATIONS OF WEGENER'S GRANULOMATOSIS,Drachman, 5 Nishino et al, 6

Exophthalmos 12 % Any cranial neuropathy 6 % Ophthalmoplegia 3-5 % Optic nerve or chiasm involvement 7 % Pituitary involvement, diabetes insipidus 4 % Cranial nerve VII palsy 4% Vestibular involvement or deafness 3 % Involvement of base of brain, meninges 7 % Cerebrovascular events 4% Ischemic stroke 3% Venous thrombosis 1% Intracerebral hemorrhage 3% Subarachnoid hemorrhage 2% Cerebritis 1.5% Seizures 3%

Neuropathy 16%o Mononeuritis multiplex 13%o Polyneuropathy 8%

Myopathy 4%

Etiology and Pathogenesis

The etiology of WG remains uncertain; however, a number of observations implicateANCA, in conjunction with intercurrent infection, in the pathogenesis. The proposedmechanism is as follows: infection leads to the production of cytokines such as interleukins1 and 8 and tumor necrosis factor alpha, which cause neutrophils to express adhesionmolecules (leading them to stick to vascular endothelium), and to express proteins thatprovide the targets for ANCA (proteinase 3 and myeloperoxidase, among others).Circulating ANCA then binds to these proteins and induces neutrophil degranulation,generation of oxygen-free radicals, and endothelial cell injury. The presence of ANCA,regardless of the specific underlying disease, is strongly associated with the humanleukocyte antigens (HLA) allele DQB*0301. By this mechanism, infection might potentiatedisease activity in WG, and there is compelling empirical evidence that this occurs.

Diagnosis

Despite the peculiar and seemingly pathognomonic nature of the WG clinical triad, theoften prolonged initial phase of the disease and its some- what protean nature provide thebasis for a broad differential diagnosis, which includes many other vasculitides; relapsingpolychondritis; lethal midline granuloma (nasopharyngeal disease, which may be caused bya limited and locally aggressive form of WG, B-cell lymphoma, and a limited form oflymphomatoid granulomatosis, also termed polymorphic reticulosis, actually a T-celllymphoma); systemic lymphomatoid granulomatosis; sarcoidosis; eosinophilic pneumonia;and a host of infectious diseases such as tuberculosis, fungal diseases, syphilis,rhinoscleroma, and leprosy. Routine laboratory abnormalities (anemia, leukocytosis,thrombocytosis, low titer rheumatoid factor) are nonspecific. The most helpful serologictest is an assay for cytoplasm or C-ANCA (related to antibodies to the serine proteinase,proteinase-3), which is 98% specific, and in active, generalized WG, has a sensitivity of96%. Sensitivity drops to 65% in initial phase or inactive disease. In contrast,antiperinuclear or P-ANCA (related primarily to antibodies to myeloperoxidase) isassociated primarily with MPA and AG. Tissue diagnosis (lung, renal, or sural nervebiopsy) is often necessary.

The diagnosis of WG is strongly supported by the histologic features of granulomatousinflammation and vasculitis in the resected tissue mass, coupled with the finding of positivecytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA).

Figure 1. Wegener granulomatosis. Histologic sections of the dura in a patient withWegener’s granulomatosis showed permeation by a dense, diffuse and focally nodulargranulomatous infiltrate composed of histiocytes, lymphocytes, plasma cells, scatteredmultinucleate giant cells (arrows), eosinophils and neutrophils. The polymorphousinfiltrate showed no cytologic features of malignancy. In several areas the granulomatousinfiltration is clearly vasocentric and focally small blood vessels showed fibrinoid necrosiswith intramural neutrophils and karyorrhectic debris, and petechial hemorrhage. Anelastic tissue stain (Verhoeff-van Gieson) showed fragmentation of the elastica, confirmingthe impression of a vasculitic granulomatous process. Special stains for bacteria,mycobacteria, and fungi were negative.

NEUROIMAGING FINDINGS IN WEGENER'S GRANULOMATOSIS

Pachymeningeal Enhancement

In Wegener granulomatosis, the meninges are considered to be abnormal (involved by thedisease) if they showed either diffuse or focal thickening on contrast-enhanced MR images.Involvement of both the tentorium cerebelli and the dura overlying the convexity of thecerebrum might occur in combination, however the tentorium cerebelli might be the solesite of involvement. In Wegener granulomatosis the condition is primarily pachymeningitisand leptomeningeal involvement by the disease is only very rarely demonstrated. Twodistinct MRI patterns of distribution of meningeal invlovement are noted in Wegenergranulomatosis (See table 3)

Table 3. Wegener granulomatosis types

Type CommentDisease contiguous withdisease of the upperairways.

Focal dural thickening and enhancement adjacent and /orcontiguous with orbital, nasal, or paranasal disease. Thisrepresent direct invasion of paranasal and para-auraltissues by the granulomatous process. Direct invasion ofthe orbit and temporal bone appears to account for orbitalpseudotumor with associated involvement of extraocularmuscles, the optic and oculomotor nerves, and deafnesscaused by labyrinthine involvement. Focal duralthickening might be nodular or linear. Nodular duralthickening might produce a mass that might requiresurgical decompression.

Disease not contiguouswith disease of theupper airways.

Diffusely abnormal meninges unrelated to sinus or orbitaldisease reflecting "metastatic disease" that is notcontiguous with disease of the upper airways. Thispachymeningitis (primarily dural invlovement) can extendwell up over the cerebral convexity or along the falx ortentorium and can account for "cerebritis" associated withseizures and focal neurologic deficits. It may also involvethe spinal canal, producing myelopathy. Duralinvolvement might be asymmetric or symmetric The duraoverlying the spinal cord might be involved in a similarfashion. Dural biopsy is diagnostic of Wegenergranulomatosis. Severe headache is the reason for referralfor MR imaging in meningeal involvement.

Figure 2. (a) Transverse and (b) coronal T1-weighted contrast-enhanced spin-echo MRimages (500/9) demonstrate diffuse symmetric linear dural thickening and enhancement(arrowheads).

Two distinct patterns of abnormal meningeal enhancement may be observed on intravenousgadolinium-enhanced MR imaging. Dural (i.e., pachymeningeal) enhancement follows the innercontour of the calvaria, whereas pial-subarachnoid (i.e., leptomeningeal) enhancement extendsinto the depths of the cerebral and cerebellar sulci and fissures. Enhancement surrounding thebrain stem is always of the pial-subarachnoid space type because the arachnoid mater is clearlyseparated from the pia by the intervening basal subarachnoid cisterns in this region. Althoughleptomeningeal enhancement has been shown to occur more commonly in the setting ofmeningitis than with neoplastic involvement, inflammatory and neoplastic processes may appearsimilar or identical on imaging studies. A diffuse, thin, regular sheetlike enhancing appearanceover the surface of the brain favors an inflammatory cause, whereas irregular, nodular meningealenhancement occurs more commonly, although not exclusively, with neoplastic subarachnoiddissemination.

Figure 3. (a) Sagittal and (b) transverse T1-weighted contrast-enhanced spin-echo MRimages (500/9) show extensive thickening and enhancement of the dura (arrows) overlyingthe thoracic spinal cord.

Figure 4. A, Coronal fat-suppressed T1-weighted contrast-enhanced spin-echo MR image(500/9) demonstrates focal thickening and enhancement of the dura (arrows) overlying theinferior aspect of both frontal lobes and contiguous with extensive nasal and paranasaldisease. B, Transverse fat-suppressed T1-weighted contrast-enhanced spin-echo MR image(500/9) shows thickening and enhancement of the dura overlying the anterior left temporallobe (arrows) contiguous with extensive paranasal disease.

Figure 5. A-C, MR images in a case of Wegener's granulomatosis with intracranialinvolvement and meningeal involvement.

Figure 6. Wegener granulomatosis. MRI T1 postcontrast images showing chronicinflammatory reaction involving the orbital fat , extraocular muscles, and lacrimal gland(A). Notice leptomeningitis demonstrated as meningeal contrast enhancement with brainedema (probably due to cerebritis). Biopsy confirmed the diagnosis in this case

Figure 7. Wegener granulomatosis, A,B CT scan showing granulomatous infiltration of theanterior fossa and the nasal cavity and on the mediastinum, C,D,E,F

Infarcts

Nonhemorrhagic infarcts that affected the cortex, white matter, or both, in a typicalvascular distribution might be seen in Wegener granulomatosis. Multiple infarctions canoccur. Ischemic brain lesions might be related to cerebral vasculitis.

Nonspecific White Matter Lesions

Nonspecific white matter lesions with high signal intensity on intermediate-weighted andT2-weighted images are occasionally seen in Wegener granulomatosis. These lesions can bemultiple and are commonly seen in the periventricular, subcortical regions, the basalganglia, the mesencephalon and pons. White matter disease - in Wegener granulomatosis-is probably ischemic in nature.

Figure 8. Transverse T2-weighted fast spin-echoMR image (3,000/105[effective]) in a patientsuspected of havingcerebral vasculitis showsan ill-defined area of highsignal intensity in thepons (arrows).

Discrete Parenchymal granulomas

Discrete parenchymal lesions with high signal intensity on intermediate-weighted and T2-weighted images, low signal intensity on T1-weighted images, and some peripheralenhancement on gadolinium-enhanced images are occasionally demonstrated in Wegenergranulomatosis

Figure 9. Transverse T2-weighted fast spin-echoMR image (3,000/105[effective]) in a patientwith gradual onset ofataxia shows a discreteright cerebellar lesion(arrow) with high signalintensity. Anintracerebralgranulomatous lesion wasthought to be the mostlikely cause because ofthe location, gradualonset of symptoms,peripheral enhancement,and improvement inataxia and reduction inthe size of the lesion aftertreatment.

Pituitary Abnormalities

Enhancement and/or enlargement of the pituitary gland are occasionally demonstrated inWegener granulomatosis. The enhancement is commonly homogeneous with thickeningand / or enhancement of the infundibulum, especially superiorly. The pituitary involvementcan occur by direct invasion of the granulomatous disease from the sphenoidal sinus orsecondary to basal pachymeningitis. Diabetes insipidus can occur when the pituitary glandis involved.

Figure 10. Coronal T1-weightedcontrast-enhanced spin-echo MRimage (500/9) in a patient withdiabetes insipidus shows diffuseenlargement of the pituitary gland(straight arrows) with thickeningand enhancement of theinfundibulum (curved arrows).There also is filling and rimenhancement (arrowheads) in thesphenoid sinuses, consistent withinflammatory disease.

Cerebral and cerebellar Atrophy

Cerebral atrophy that is more marked than expected given the patients age can bedemonstrated in Wegener granulomatosis. Cerebral atrophy usually ranges from mild tomoderate. Atrophy can also involve the cerebellum. Patients with cerebral atrophycommonly have symptoms suggestive of cerebral vasculitis, including peculiar intellectualaffect, headaches, confusion, and transient neurologic events such as paraesthesia,blackouts, and visual loss.

Table 4. Types of CNS involvement in Wegener granulomatosis

Type CommentPachymeningealEnhancement

In Wegener granulomatosis, the meninges are considered to beabnormal (involved by the disease) if they showed either diffuse orfocal thickening on contrast-enhanced MR images. Involvement ofboth the tentorium cerebelli and the dura overlying the convexityof the cerebrum might occur in combination, however thetentorium cerebelli might be the sole site of involvement

Infarcts Nonhemorrhagic infarcts that affected the cortex, white matter, orboth, in a typical vascular distribution might be seen in Wegenergranulomatosis. Multiple infarctions can occur. Ischemic brainlesions might be related to cerebral vasculitis.

Nonspecific WhiteMatter Lesions

Nonspecific white matter lesions with high signal intensity onintermediate-weighted and T2-weighted images are occasionallyseen in Wegener granulomatosis. These lesions can be multiple andare commonly seen in the periventricular, subcortical regions, thebasal ganglia, the mesencephalon and pons. White matter disease -in Wegener granulomatosis- is probably ischemic in nature.

PituitaryAbnormalities

Enhancement and/or enlargement of the pituitary gland areoccasionally demonstrated in Wegener granulomatosis. Theenhancement is commonly homogeneous with thickening and / orenhancement of the infundibulum, especially superiorly.

Cerebral andcerebellar Atrophy

Cerebral atrophy that is more marked than expected given thepatients age can be demonstrated in Wegener granulomatosis.Cerebral atrophy usually ranges from mild to moderate. Atrophycan involve the cerebellum.

DISCUSSION

In a 1963 literature review of 104 patients with Wegener granulomatosis, Drachman (5)identified three processes of nervous system involvement. First, vasculitis occurred in 29(28%) patients and produced mononeuritis multiplex, polyneuritis, myopathy,intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral arterial or venousthrombosis. Second, granulomatous lesions resulting from contiguous invasion from nasal,paranasal, or orbital disease and involving the optic nerve, optic chiasm, pituitary, nasalvestibule, base of the brain, and meninges were present in 27 (26%) patients. Third,granulomatous lesions remote from nasal granulomas and involving the meninges, cranialnerves, brain, and parietal bone were described in four (4%) patients.

Because cerebral and meningeal involvement by Wegener granulomatosis is rare, with areported prevalence of 2%–8% (1,4,6), there are few reports of small series (7,8) in whichthe MR imaging appearances were described. Asmus et al (7) reported the MR imaging

findings in seven patients: Six patients had small, sometimes multiple, focal areas ofincreased signal intensity in the white matter on T2-weighted images, and one had aninfarct. Provenzale and Allen (8) reported the computed tomographic (two patients) andMR imaging (five patients) findings in seven patients, which included dural thickening andcontrast enhancement in three patients, infarcts in two, areas of high signal intensity in thewhite matter on T2-weighted MR images in two, and abnormal high signal intensity in thebrainstem on T2-weighted MR images in two. Direct intracranial spread from nasal,paranasal, or orbital disease or remote, discrete granulomatous lesions in brainparenchyma were not reported in either series.

Remote granulomatous involvement of the meninges in Wegener granulomatosis is rare (4–6,10). At postmortem examination in one of 104 patients in Drachman's review (5),meningeal involvement by a necrotic and granulomatous process was observed. Nishino etal (6,10) reported that only one of 324 patients with Wegener granulomatosis hadthickening and enhancement of the right tentorium cerebelli, which caused multiple cranialneuropathies and severe headaches. None of 85 patients described by Fauci et al (4) hadmeningeal involvement with Wegener granulomatosis. The typical MR imaging appearanceis that of bilateral diffuse symmetric linear dural thickening and enhancement. Suchfindings were described by Provenzale and Allen (8) in three patients, although focal andnodular thickening have also been previously reported (11). Large areas of high signalintensity in the white matter underlying thickened meninges on T2-weighted images havebeen previously noted (11,12). Diffuse dural thickening and enhancement might occur bothintracranially and overlying the thoracic cord. Spinal dural thickening might producemyelopathy. There is one previous report (10) of dural thickening overlying the thoraciccord in a case of Wegener granulomatosis, and this resulted in a subacute myelopathy.

Leptomeningeal thickening and enhancement overlying the sulci in addition to duralenhancement is quite rare and to our knowledge, this radiologic finding has rarely beenreported, although thickening, fibrosis, and numerous granulomas that often surround theinvolved blood vessels, as seen at histologic examination of the pia-arachnoid, have beenreported (11).

The differential diagnosis for diffuse symmetric linear meningeal thickening is broad andincludes neurosarcoid, primary dural tumors such as lymphoma and meningioma,metastases, infectious meningitis, neurosyphilis, and hypertrophic cranial pachymeningitis.In neurosarcoid, the pia is involved more frequently than the dura (13). Clinical evaluationand laboratory and radiologic investigations help the radiologist determine the most likelydiagnosis, although biopsy may be necessary for confirmation.

Direct intracranial invasion from adjacent extracranial disease has been reported (5,14) tobe the most common means by which the central nervous system is involved with Wegenergranulomatosis. This commonly occurs as extensive nasal, paranasal, or orbital diseasespreading intracranially to adjacent dura.

The ability to acquire multiplanar images without irradiating the eyes makes MR imagingan excellent modality for demonstration of subtle intracranial spread from nasal,

paranasal, or orbital disease. Because thickened dura can be difficult to differentiate fromcerebrospinal fluid on T2-weighted images, we advocate the use of fat-suppressed T1-weighted MR imaging with gadolinium enhancement when direct spread is suspected.

Vasculitis most frequently affects the peripheral nervous system, causing mononeuritismultiplex or polyneuritis; it involves the brain or meninges in 0%–6% of patients, causingintracerebral hemorrhage, subarachnoid hemorrhage, and cerebral arterial or venousthrombosis (4–6). These hemorrhagic complications are thought to be secondary toweakening of blood vessel walls by means of an inflammatory vasculitis, resulting in vesselrupture and bleeding. Patients with WG might have symptoms suggestive of vasculitis,such as altered consciousness or altered affect, or symptoms suggestive of ischemicepisodes, such as paraesthesia, blackouts, or internuclear ophthalmoplegia.

Patients with WG might have nonspecific areas of high signal intensity were seen in thewhite matter on intermediate-weighted and T2-weighted MR images and most probablythese white matter lesions are ischemic in nature and this is consistent with vasculiticgranulomatous nature of WG. There are several other possible causes of infarct in cases ofWegener granulomatosis: arterial occlusion secondary to a granulomatous mass thatextends from nasal or paranasal sites into the skull base (15), emboli from maranticendocarditis (8), infarct secondary to renal failure–induced hypertension, and other causesunrelated to Wegener granulomatosis.

Remote granulomatous lesions in brain parenchyma are the least common form of centralnervous system involvement with Wegener granulomatosis (5), although there have been afew reported cases (16–18). Patients may present with seizures, and the lesions may besingle or multiple (17,18). Homogeneous and ring enhancement have been demonstrated,and the lesions have high signal intensity on T2-weighted MR images and have been shownto either decrease in size or disappear with treatment (17). Cerebral granulomas have beenfound to be dark brown, scarred, indurated, and poorly demarcated at surgery and tocontain plasma cells, lymphocytes, histiocytes, and giant cells at histologic examination(18).

Multiple nonspecific lesions with increased signal intensity on intermediate-weighted andT2-weighted MR images are seen in the white matter in many conditions, includingpostinfectious encephalitis, viral infections, sarcoidosis, multiple sclerosis, Behçetsyndrome, and the leukodystrophies, and are commonly seen in the elderly. This whitematter pathology might have ischemic aetiology and this is supported by the pathologicalimpression that granulomatous infiltration in WG is clearly vasocentric (Fig. 1c) andfocally - in white matter lesions- small blood vessels commonly show fibrinoid necrosis withintramural neutrophils and karyorrhectic debris.

However the exact etiology of white matter lesions in relation to Wegener granulomatosis isunclear. Similar white matter lesions in cases of Wegener granulomatosis have also beenreported by Provenzale and Allen (8) and Asmus et al (7). Asmus et al reported that theseareas represented areas of microinfarct, and Drachman (5) reported the postmortemexamination finding of small (<4 x 6-mm) areas of infarct in the thalamus, cortex,

mesencephalon, pons, and subcortical white matter in a patient with cerebral vasculitissecondary to Wegener granulomatosis.

The pituitary and infundibulum may be involved in Wegener granulomatosis by means ofdistant granulomas or direct spread. Four patients in Drachman's series (5) hadinvolvement of the pituitary gland due to direct extension from nasal, paranasal, or orbitaldisease that caused diabetes insipidus. Czarnecki and Spickler (19) reported a case ofdiabetes insipidus and hyperprolactinemia; this was probably secondary to remotegranulomatous involvement with Wegener granulomatosis because there was no evidenceof direct extension from extracranial disease. MR imaging demonstrated a sellar mass,absence of the posterior pituitary high-signal-intensity spot, and thickening andenhancement of the infundibulum, with almost complete resolution of findings at repeatimaging performed 2 months after treatment with high-dose steroid therapy (19). Ingeneral in patients with diffuse enlargement of the pituitary gland and infundibularthickening, it is impossible to be certain whether this represented distal granulomatousinvolvement with Wegener granulomatosis or direct spread from extensive inflammatorychanges in the sphenoid sinus, even when floor of the pituitary fossa appears to be intact inboth patients.

Finally, the exact etiology of brain atrophy in cases of Wegener granulomatosis is unclear,but possible explanations include cerebral vasculitis, drugs used in treatment (eg, steroids),and other unrelated causes such as senile atrophy. Yamashita et al (20) reported thedevelopment of cerebral atrophy over 6 months in a patient with cerebral vasculitissecondary to Wegener granulomatosis.

In summary, in patients with cerebral and meningeal involvement with Wegenergranulomatosis, there is a wide spectrum of MR imaging findings, which reflect the threemeans by which the central nervous system can be affected in this disease: vasculitis; directspread from adjacent disease in the nasal, paranasal, or orbital region; and remotegranulomatous lesions. MR imaging, with which it is possible to acquire multiplanarimages without radiation, is an excellent modality for demonstration of theseabnormalities, especially for evaluation for direct spread to the meninges from orbital,nasal, or paranasal disease.

Treatment of Wegener granulomatosis

The 2-year case fatality rate in untreated WG is 93%. Optimal treatment consists of dailyintravenous or oral cyclophosphamide, 2 mg/kg/day Monthly pulse intravenouscyclophosphamide, preferred because of its better side-effect profile, is insufficient toreliably induce remission but may be employed to sustain remission. Cyclophosphamidetreatment is generally maintained through 1 year of stable remission. Daily prednisone, 1mg/kg/day is routinely employed during the first 6- 12 months. With this approach,Hoffman et al (1) achieved marked improvement or partial remission in 91 % of patientsand complete remission in 75%. The high morbidity rate associated with this treatment(infections, hemorrhagic cystitis, secondary neoplasia) has led to an avid search foralternative approaches. Methotrexate is successfully employed to induce remission in

patients who present with relatively more indolent disease and may be effective insustaining remission. Cotreatment of patients on cyclophosphamide regimens withtrimethoprim-sulfamethoxazole (Bactrim, Septra) significantly reduces the rate of relapse.

Initially, WG was uniformly fatal within a few months of diagnosis; the prognosis wasminimally improved after institution of steroid therapy.

Cyclophosphamide has since been used very effectively and is the usual drug of choice forinduction of remission. The well-recognized toxicity of oral cyclophosphamide has lead toinstitution of pulse therapy as the present standard of care.

Azathioprine may be used as maintenance therapy or as initial therapy in patients unableto tolerate cyclophosphamide.

Less frequently employed therapies include methotrexate. Excellent remission is achievedin about 70% of patients but unfortunately relapses are common. Aggressive treatment ofpulmonary and renal involvement at the time of disease onset seems to lessen theprobability of later neurologic involvement.

References

1. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of158 patients. Ann Intern Med 1992; 116:488-498.

2. Anderson JM, Jamieson DG, Jefferson JM. Non-healing granuloma and the nervoussystem. Q J Med 1975; 44:309-323.

3. DeRemee RA, McDonald TJ, Harrison EG, Jr, Coles DT. Wegener'sgranulomatosis: anatomic correlates, a proposed classification. Mayo Clin Proc1976; 51:777-781.

4. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospectiveclinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med1983; 98:76-85.

5. Drachman DA. Neurological complications of Wegener's granulomatosis. ArchNeurol 1963; 8:145-155.

6. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurologicalinvolvement in Wegener's granulomatosis: an analysis of 324 consecutive patients atthe Mayo Clinic. Ann Neurol 1993; 33:4-9.

7. Asmus R, Koltze H, Muhle C, et al. MRI of the head in Wegener's granulomatosis.Adv Exp Med Biol 1993; 336:319-321.

8. Provenzale JM, Allen NB. Wegener granulomatosis: CT and MR findings. AJNR1996; 17:785-792.

9. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101-1107.

10. Nishino H, Rubino FA, Parisi JE. The spectrum of neurologic involvement inWegener's granulomatosis. Neurology 1993; 43:1334-1337.

11. Tishler S, Williamson T, Mirra SS, Lichtman JB, Gismondi P, Kibble MB. Wegenergranulomatosis with meningeal involvement. AJNR 1993; 14:1248-1252.

12. Weinberger LM, Cohen ML, Remler BF, Naheedy MH, Leigh RJ. IntracranialWegener's granulomatosis. Neurology 1993; 43:1831-1834.

13. Sherman JL, Stern BJ. Sarcoidosis of the CNS: comparison of unenhanced andenhanced MR images. AJNR 1990; 11:915-923.

14. Goldberg AL, Tievsky AL, Jamshidi S. Wegener granulomatosis invading thecavernous sinus: a CT demonstration. J Comput Assist Tomogr 1983; 7:701-703.

15. Satoh J, Miyasaka N, Yamada T, et al. Extensive cerebral infarction due toinvolvement of both anterior cerebral arteries by Wegener's granulomatosis. AnnRheum Dis 1988; 47:606-611.

16. Castleman B, Towne VW. Wegener's granulomatosis. Massachusetts GeneralHospital Case Records, case 37511. N Engl J Med 1951; 245:978-985.

17. Miller KS, Miller JM. Wegener's granulomatosis presenting as a primary seizuredisorder with brain lesions demonstrated by magnetic resonance imaging. Chest1993; 103:316-318.

18. Oimomi N, Suehiro I, Mizuno N, Baba S, Okada S, Kanazawa Y. Wegener'sgranulomatosis with intracerebral granuloma and mammary manifestation. ArchIntern Med 1980; 140:853-854.

19. Czarnecki EJ, Spickler EM. MR demonstration of Wegener granulomatosis of theinfundibulum, a cause of diabetes insipidus. AJNR 1995; 16(suppl 4):968-970.

20. Yamashita Y, Takahashi M, Bussaka H, Miyawaki M, Tosaka K. Cerebralvasculitis secondary to Wegener's granulomatosis: computed tomography andangiographic findings. J Comput Assist Tomogr 1986; 10:115-120.

The author

Professor Yasser Metwally

www.yassermetwally.com