Clin Rheumatol (2006) 25: 739–742DOI 10.1007/s10067-005-0065-5

CASE REPORT

Radek Špíšek . Elena Kolouchová . Jiří Jenšovský .Robert Rusina . Pavel Fendrych . Jaroslav Plas .Jiřina Bartůňková

Combined CNS and pituitary involvement as a primarymanifestation of Wegener granulomatosis

Received: 31 March 2005 / Accepted: 6 April 2005 / Published online: 2 December 2005# Clinical Rheumatology 2005

Abstract Wegener granulomatosis (WG) is a systemicvasculitis of small and medium vessels. It predominantlyaffects the upper and/or lower respiratory airway and kid-neys. Its pathogenesis is not fully understood. WG relativelyfrequently affects the nervous system (in 30–50% accordingto the different studies). Most frequently, it manifests asnecrotizing vasculitis that leads to the peripheral neurop-athies or to the cranial nerves palsy. Impairment of thecentral nervous system (CNS) is less frequent and occurs in2–8% of patients. Three major pathogenetic mechanismswere described: CNS vasculitis, spreading of granulomasfrom the adjacent anatomical areas (paranasal cavities, orbitetc.), and new formation of granulomas in brain tissue. Thiscase report describes patients in whom WG manifested in

the form of localized skin involvement and combined CNSinvolvement that included pituitary gland. Atypical presen-tation of WG impedes and slows down the process ofdiagnosis and emphasizes the need for collaboration be-tween medical specialists.

Keywords Case report . CNS . Diabetes insipidus .Panhypopituitarismus . Wegener granulomatosis

Introduction

Wegener granulomatosis (WG) is a systemic vasculitis ofmedium, small arteries, venules, arterioles, and, occasion-ally, large arteries. It was initially reported in 1931 and laterdescribed in more details by F. Wegener. In its classicpresentation, it primarily affects the upper and/or lowerrespiratory airway and kidneys. A limited form of WG hasclinical findings restricted to the upper respiratory tract andlungs. However, 80% of patients subsequently developrenal involvement. Pathophysiology of WG is not elu-cidated. Pathogenetic process starts with the injury andsubsequent necrosis of the vessels that evolves into nec-rotizing granuloma. Gradual evolution from granuloma tothe vasculitis may be an important step in understandingthe possible etiology and pathogenesis of WG. Cellularimmune processes are likely important in granulomatousinflammation. However, the discovery of antibodies to cy-toplasmic antigens within neutrophils [antineutrophiliccytoplasmic antibody (ANCA) designated C-ANCA fordiffuse cytoplasmic staining and P-ANCA for perinuclearstaining by immunofluorescence] in most patients withWG raises the possibility of humoral autoimmunity. This iseven more likely with the demonstration of the presence ofserine proteinase 3, the predominant antigen for C-ANCA,on the surface of activated endothelial cells. There isevidence that C-ANCA directed against serin proteinase 3can directly contribute to the pathogenesis of the disease[1].

Most patients with either classical or limited form ofWGpresent with the involvement of upper respiratory tract and

R. Špíšek (*) . J. BartůňkováDepartment of Immunology, 2nd Faculty of Medicine,Charles University,V Uvalu 84,150 06 Prague 5, Czech Republice-mail: radek.spisek@lfmotol.cuni.czTel.: +420-224-435963Fax: +420-224-435962

E. KolouchováAlergology and Immunology Clinic,Benešov, Czech Republic

J. JenšovskýDepartment of Clinical Endocrinology,Central Military Hospital,Prague, Czech Republic

R. RusinaDepartment of Neurology, Thomayer’s Teaching Hospital,Prague, Czech Republic

P. FendrychDepartment of Magnetic Resonance,Institute of Clinical and Experimental Medicine,Prague, Czech Republic

J. PlasDepartment of Neurosurgery, Charles University,1st Medical School, Central Military Hospital,Prague, Czech Republic

lungs. Renal involvement is also common, manifesting asacute renal failure or acute nephritis, sometimes withnephrotic-range proteinuria. Patients may also present witha clinical picture of rapidly progressive glomerulonephritis.In some cases, renal involvement may not be clinicallydetectable. Other organs and systems that may becomeinvolved are the joints, eyes, skin, nervous system, heart,and, less commonly, the gastrointestinal tract, subglottis ortrachea, lower genital urinary tract, parotid glands, thyroidgland, and liver. Pathologically, the pulmonary features ofWG are necrotizing granulomatous pulmonary inflamma-tion, and, occasionally, alveolar capillaritis. The formerresults in nodular densities and lung infiltrates, and thelatter results in diffuse pulmonary hemorrhage. The glo-merulonephritis is characterized by focal necrosis andcrescent formation without immunoglobulin or comple-ment deposition, also called pauci-immune glomerulone-phritis [2].

WG is associated with a very high mortality rate (>90%)if it remains untreated. Modern and aggressive immuno-suppressive treatment improved prognosis. In a 1996 study,Matteson et al. [3] reported mortality rates of 28% at 5 yearsand 36% at 10 years. A retrospective study by Booth et al.[4], published in 2003, demonstrated a cumulative 5-yearsurvival rate of 76% and a 1-year mortality rate of 18%.

Neurologic involvement is quite frequent. Frequency ofnervous system involvement in patients with WG isestimated to range between 25 and 50% [2]. Peripheralneuropathies are the most common form. Cerebral andmeningeal involvement is much less frequent and variesbetween 2 and 8% according to the different studies [5].Pituitary gland involvement is extremely rare. Here, wereport a patient who presented with a localized centralnervous system (CNS) and pituitary gland involvement asthe primary manifestations of WG.

Case report

A 29-year-old previously healthy man was examined fromthe beginning of 2002 for repeated skin abscesses, weight

loss (15 kg in 3 months), collapses, and erectile dysfunc-tion. Endocrinological investigation revealed clinical signsof hypogonadism, loss of pubic hair, hypotension, dry skin,and periorbital edema. Laboratory findings showed panhy-popituitarism, low adrenocorticotropin-releasing hormone(ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone(LH) and deficit of peripheral hormones. Insulin testfurther revealed growth hormone deficiency, low insulin-like growth factor (IGF)-I concentration. Brain magneticresonance imaging (MRI) showed a cystic lesion in thesellar region. In September 2003, the patient underwent aneurosurgical revision. Because of the atypical features ofthe infiltrative lesion, only a biopsy specimen was taken,and the cystic mass was left in situ. Histology revealedcellular infiltrate with the presence of eosinophils, frag-ments of neutrophils, and microabscesses. Immunologicalfindings repeatedly showed positivity of C-ANCA specificfor PR3. WG was suspected based on these findings. Afterthe normalization of metabolic parameters, initiation ofsubstitution of anterior and posterior pituitary insufficien-cy, and a low-dose oral prednisone, patient was in a sat-isfactory clinical condition. However, he intermittentlycomplained of headaches and epistaxis. In April 2004, hewas admitted to the hospital for diplopy, severe headache,left eyelid ptosis, and complete left-sided opthtalmoplegia.MRI scans showed only mild periventricular and subcor-tical atrophy without any foci. High-dose methylprednis-olone (3×250 mg) was administered, and the patientimproved. After a short symptoms-free period, he devel-oped signs of acute psychosis. In June 2004, he was thusreadmitted to the hospital. Disorders of recent memory andorientation, apraxia, and confusion were the predominantclinical features, together with hyperreflexia and mildpyramidal tract involvement. MR scan this time showedseveral areas of increased signal intensity in the insularregion, pons, and basal ganglia in T2-weighted sequences;the brainstem lesion was hypointense in T1 with noenhancement (Fig. 1). The diagnosis of probable cerebralvasculitis as a presentation of WG was made, and a pulsetherapy with cyclophosphamide was initiated. Patient rap-

Fig. 1 MRI of the brain at thetime of the admission to thehospital with the symptoms ofacute psychosis. a TransverseT2-weighted MR image show-ing high signal intensity in thepons (arrow). b Sagittal T1-weighted MR image showing alesion of low intensity in thepons not enhancing after con-trast administration (whitearrow) and inflammatory lesionof high signal intensity inpituitary gland enhancing aftercontrast (black arrow)

740

idly improved and is now followed up on the outpatientbasis. He has completely recovered from his neurologicinvolvement and returned to former professional and socialactivities. Control MR scans performed 2 months after theinitiation of cyclophosphamide therapy revealed a signif-icant reduction of the mentioned cerebral lesions (notshown).

Discussion

Clinical and laboratory picture of the disease in this patientmost probably corresponds to the WG whose symptomswere primarily limited to the skin. In the last 2 years, thedisease progressed and involved CNS. This is supported bythe positivity of PR3-specific C-ANCA, by the histologicalfindings in the pituitary biopsy and favorable outcome afterthe initiation of adequate immunosuppressive treatment.WG relatively frequently affects the nervous system (in30–50% according to the different studies). Most fre-quently, it manifests as necrotizing vasculitis that leads tothe peripheral neuropathies or cranial nerve palsy [6].Peroneal nerve, tibial nerve, sural nerve, and ulnar nerveare among the most frequently affected. Concerning cranialnerves, WG most often impairs the function of the second,sixth, and seventh cranial nerve. Peripheral nerves aredamaged either directly by the vasculitic process or com-pressed by granulomas. CNS involvement is much lessfrequent and is estimated to occur in approximately 2–8%patients. Three major pathogenetic mechanisms were de-scribed: CNS vasculitis, spreading of granulomas from theadjacent anatomical areas (paranasal cavities, orbit), anddirect formation of granulomas in cerebral tissue [7].Vasculitis affects brain and meninges and can lead to thecerebral hemorrhage, to the subarachnoid hemorrhage, andalso to the arterial or venous trombosis. Hemorrhagiccomplications are probably secondary due to the weaken-ing of cell wall by the inflammatory process that eventuallyleads to the rupture. Clinical symptoms are extremelyvariable. Most frequently, patients complain of severeheadaches. But CNS involvement also manifests as loss ofconsciousness, affective disorders, and transient or perma-nent ischemic attacks. According to the level of brain tissuedamage, MR shows developed infarcts or only nonspecificwhite matter lesions. Formation of granulomas in thecerebral tissue is very rare. Granulomas in CNS can presentas seizures, and they can be multiple [8]. Histologicalstudies on cerebral granulomas were done only in a verylimited number of patients. Granulomas usually containplasma cells, lymphocytes, and histiocytes [9]. Our patientinitially presented with the predominant involvement ofpituitary gland. It is even less frequent than CNS in-volvement. If present, it most frequently presents as acentral diabetes insipidus (DI) [10]. Concurrent impairmentof the anterior lobe of pituitary gland was reported inapproximately half of the patients with DI. Hyperprolac-tinemy is a frequent finding [10, 11]. It is also conceivablethat anterior lobe dysfunction (hypothyroidism, hypocor-ticalism, and hypogonadism) is more frequent and is under-

diagnosed because some symptoms may be mitigated bythe treatment, especially by corticosteroids. There are about15 reports of WG-associated DI. DI developed as a firstmanifestation before the involvement of lungs and kidneysin 25% of these patients. The rest of the patients developedDI months or years after the initial diagnosis of WG.Typical MR findings in pituitary involvement includeinfundibular thickening and the absence of hyperintensesignal that is normally present in the posterior lobe on theT1-weighted scans. Cystic enlargement of pituitary gland isalso a frequent finding [7, 12]. It is not known whetheradequate therapy and an early induction of remission couldlead to the recovery of pituitary function. It was suggestedby several reports [13, 14]; however, in most of the cases,the impairment is irreversible because of the extensivenecrosis [15]. It is therefore necessary to include WG intothe differential diagnosis of the causes of panhypopituita-rism. Investigation of ANCA can be a helpful diagnosticmarker; however, it is important to note that negativity ofANCA does not exclude the diagnosis of WG. As much as50% of patients with limited forms of WG do not haveANCA in the serum [1].

Cerebral atrophy, described on MR scans of our patient,is not a rare finding in WG with CNS involvement as it hasbeen described in half of the patients. There are severalfactors participating on its etiology. Cerebral vasculitis andsome of the drugs used for the treatment, especially cor-ticosteroids, are certainly the important factors.

The presented case report documents an unusualpresentation of WG. Atypical presentations of WG, as inthis case, impedes and slows down the diagnostic processand emphasizes the need for collaboration between medicalspecialists.

Acknowledgement This work was supported by the grant MSM0021620812 provided by the Ministry of Education.

References

1. Bartunkova J, Tesar V, Sediva A (2003) Diagnostic andpathogenetic role of antineutrophil cytoplasmic autoantibodies.Clin Immunol 106:73–82

2. Fauci AS, Haynes BF, Katz P, Wolff SM (1983) Wegener’sgranulomatosis: prospective clinical and therapeutic experiencewith 85 patients for 21 years. Ann Intern Med 98:76–85

3. Matteson EL, Gold KN, Bloch DA, Hunder GG (1996) Long-term survival of patients with Wegener’s granulomatosis fromthe American College of Rheumatology Wegener’s granulo-matosis classification criteria cohort. Am J Med 101:129–134

4. Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GHet al (2003) Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 41:776–784

5. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE(1993) Neurological involvement in Wegener’s granulomatosis:an analysis of 324 consecutive patients at the Mayo Clinic. AnnNeurol 33:4–9

6. Nishino H, Rubino FA, Parisi JE (1993) The spectrum ofneurologic involvement in Wegener’s granulomatosis. Neurol-ogy 43:1334–1337

7. Murphy JM, Gomez-Anson B, Gillard JH, Antoun NM, CrossJ, Elliott JD et al (1999) Wegener granulomatosis: MR imagingfindings in brain and meninges. Radiology 213:794–799

741

8. Miller KS, Miller JM (1993) Wegener’s granulomatosis present-ing as a primary seizure disorder with brain lesions demonstratedby magnetic resonance imaging. Chest 103:316–318

9. Oimomi M, Suehiro I, Mizuno N, Baba S, Okada S, KanazawaY (1980) Wegener’s granulomatosis with intracerebral granu-loma and mammary manifestation. Report of a case. ArchIntern Med 140:853–854

10. Miesen WM, Janssens EN, van Bommel EF (1999) Diabetesinsipidus as the presenting symptom of Wegener’s granuloma-tosis. Nephrol Dial Transplant 14:426–429

11. Katzman GL, Langford CA, Sneller MC, Koby M, Patronas NJ(1999) Pituitary involvement by Wegener’s granulomatosis:a report of two cases. AJNR Am J Neuroradiol 20:519–523

12. Provenzale JM, Allen NB (1996) Wegener granulomatosis: CTand MR findings. AJNR Am J Neuroradiol 17:785–792

13. Haynes BF, Fauci AS (1978) Diabetes insipidus associated withWegener’s granulomatosis successfully treated with cyclophos-phamide. N Engl J Med 299:764

14. Hurst NP, Dunn NA, Chalmers TM (1983) Wegener’s granu-lomatosis complicated by diabetes insipidus. Ann Rheum Dis42:600–601

15. Garovic VD, Clarke BL, Chilson TS, Specks U (2001) Diabetesinsipidus and anterior pituitary insufficiency as presentingfeatures of Wegener’s granulomatosis. Am J Kidney Dis 37:E5

742