HISTORY OF THE CASE
A 75-year-old woman was admitted to the hospital because of weakness and a tendency to fall.
Eight months earlier, a temporal-artery biopsy, with negative results, had been performed elsewhere because of frequent headaches and an elevated erythrocyte sedimentation rate. Magnetic resonance imaging (MRI) of the brain at that time showed enhancement by gadolinium of the cerebellar tentorium, which was more prominent on the right side, in the posterior middle cranial fossa and posterior fossa, without mass effect or evidence of obstruction. Soon thereafter; esophagogastroduodenoscopic and colonoscopic examinations revealed active gastritis, for which the patient received omeprazole. Two months later, her memory deteriorated, and she began to dress carelessly. Three months before admission, she experienced vague dizziness and had a tendency to fall; she began to walk with a cane. Two weeks before admission, she fell in the bathtub and remained there all night because of generalized weakness. One day before admission, she again fell, striking her occiput and lying on the floor for two hours because of diffuse weakness. She was brought to this hospital.
1 The patient had had endometrial cancer 16 years before admission, which was treated with a hvsterectomy and radiotherapy. Six years later, a partial colectomy with a colostomy was performed because ofcolonic carcinoma.
The temperature was 36.4°C, the pulse was 61, and the respirations were 20. The blood pressure was 165/85 mm Hg.
On examination, the patient was somnolent. A grade 3 systolic murmur was heard along the sternal border, and it radiated to the axilla. A functioning right-sided colostomy was present. On neurologic examination, she was oriented to the city and knew she was in a hospital, which she could not identify. Her attention span was short. Her ability to name objects was preserved, but she could not recall three objects after five minutes. There was fine nystagmus on right lateral gaze. Hearing was impaired bilaterally. A slight left-sided facial droop was noted. There was no other evidence of cranial-nerve dysfunction. Muscle strength was slightly reduced in the left arm and leg. Fine finger movements became smaller when sustained. The patient held on to furniture while walking and had a tendency to lean to the left. Retropulsion was present. She was unstable on standing. She refused testing of the deep-tendon reflexes. Bilateral grasp reflexes were observed; the plantar responses were flexor.
The urine was normal. Laboratory tests were performed (Tables 1 and 2). An electrocardiogram showed a normal rhythm at a rate of 60, with delayed R-wave progression in leads V1through V5. A computed tomographic (CT) scan of the brain (Fig. 1) revealed thickening and increased density of the tentorium and of the dura overlying the left cerebellar hemisphere, with dense enhancement. The right lateral and third ventricles were dilated, and transependymal edema surrounded the right lateral ventricle; no obstructive lesion was identified. Omeprazole was administered, and phenytoin sodium was subsequently added.
On the second hospital day, a gadolinium-enhanced MRI study of the brain (Fig. 2 and 3) revealed thickening of the tentorium and left cerebellar dura that was isointense on Ti-weighted images, hypo-intense on T,-weighted images, and partly enhanced. The right lateral and third ventricles were dilated, with edema surrounding the right lateral ventricle. T2-weighted images showed hyperintense foci in the pons, right thalamus, and periventricular white matter. No flow void was detected in the infraclinoid portion of the left internal carotid artery. A lumbar puncture was performed (Table 3). A CT scan of the thorax (Fig. 4) showed patchy ground-glass opacities throughout both lungs and subpleural nodular opacities, 2 to 3 mm in diameter, in the superior segment of the left lower lobe and in the posterior right middle lobe, with calcified precarinal and subcarinal lymph nodes, 5 to 10 mm in diameter. ACT scan of the abdomen, obtained after the administration of contrast material, showed punctate calcifications throughout the liver and spleen, gallstones, and bilateral renal cysts.
On the sixth hospital day, laboratory tests were performed (Table 2). On the 10th day, the patient became more disoriented and lethargic, required assistance to stand, and had an ataxic gait. The results of a tuberculin skin test (purified protein derivative, 5 TU) were strongly positive.
On the 13th hospital day, the patient was stuporous. She awakened only briefly in response to noxious stimulation and moved the right arm and leg more vigorously than the left. All deep tendon reflexes were diminished. The results of a urinalysis were normal. Laboratory tests were performed (Tables I and 4). Radiographs of the chest were unremarkable.
On the next day, a ventriculostomy was performed, and vancomycin was administered intravenously. The cerebrospinal fluid was examined (Table 3). Microscopical examination of biopsy specimens of the meninges (Fig. 5) showed granulomatous pachvmeningitis, with numerous ill-defined collections of epithelioid histiocvtes and multinucleated giant cells without necrosis. Special stains showed no mycobacteria, fungi, or other microorganisms. The leptomeninges contained scattered inflammatory cells; cerebellar tissue in the specimen was normal. During the next few days, the patient became more alert and communicative. On the 17th day, laboratory tests were performed (Tables 1 and 2). All culture specimens were negative.
A diagnostic procedure was performed.
DR. JOHN SHMIDT: This woman's illness was heralded by headaches, then progressed indolently over a period of eight months to affect both her mind and her gait. By the time of admission, an encephalopathy had developed that was characterized by clouded consciousness, postural instability, diminished hearing with asymmetric nvstagmus, and a left hemiparesis.
The first question is whether this complicated clinical picture can be attributed to a single pathologic entity. I believe that it can, and my working hypothesis will be that the patient's clinical presentation represents the neurologic manifestation of a process that generally affects the lungs.
May we review the imaging studies?
DR. PAMELA W. SCHROFF: On a CT scan of the head obtained after the administration of contrast material (Fig. 1), the tentorium appears thickened, with dense enhancement. An MRI scan (Fig. 2 and 3) shows that the tentorium and the dura overlying the left cerebellar hemisphere and part of the right cerebellar hemisphere are isointense in relation to the brain on Ti weightedimages and hvpointense on Ty weighted images, withMense enhancement after the administration of gadolinium. There is no leptomeningeal enhancement. The right lateral and third ventricles are dilated, with edema surrounding the right lateral ventricle. There is no evidence of sinusitis. A CT scan of the chest (Fig. 4) shows bilateral, diffuse, patchy ground-glass opacities; calcified mediastinal nodes, 1 cm in diameter; and scattered, tiny subpleural nodules.
DR. SHMIDT: Hydrocephalus and meningitis can account for the neurologic findings in this case. In view of the evidence of transependvmal edema and sulcal effacement, the marked dilatation of the right lateral ventricle must reflect an increase in intraventricular pressure rather than a loss of hemispheric tissue. Features of the patient's encephalopathv are consistent with increased intracranial pressure, and the left hemiparesis is probably due to compromise of the contralateral corticobulbar and corticospinal tracts in the periventricular white matter of the right hemisphere. Meningitis might be a factor in the patient's hearing loss, but support for this interpretation requires more information about whether the deficit is conductive, sensorineural, or both.
Although it seems certain that the meningitis caused the hydrocephalus, the causal mechanism is unclear. An initial consideration is a blockage of the flow of cerebrospinal fluid by leptomeningeal inflammation at the level of the thickened tentorium, at the base of the brain, or at both sites, but the normal sizes of the fourth ventricle and aqueduct argue against this explanation. Moreover, an extraventricular obstruction would not account for the asymmetry of the lateral ventricles. If the asymmetry had been partly congenital or due to a previous injury, it should have been seen on the MRI scan obtained eight months before admission. Experimental and clinical evidence has implicated impaired cerebral venous drainage in the pathogenesis of hydrocephalus. Since the periosteal and meningeal lavers of the dura split to form venous sinuses, perhaps inflammation of the tentorium caused narrowing or thrombosis of the straight sinus, but the MRI scan does not show either abnormality. Also, there is now a general consensus that venous insufficiency is not an important mechanism in the development of hydrocephalus
Another explanation of the hydrocephalus is based on the concept that ventricular enlargement is partly determined by the difference in pressure between the ventricle and the overlying subarachnoid compartment.' If meningeal exudate were to obliterate the subarachnoid space over the right hemisphere, the resulting elevation of the transmural pressure gradient across the right cerebral mantle might contribute to right ventricular dilatation, but again, the MRI scan does not show this change, and the cortical subarachnoid spaces appear normal. I am left with the view that there must be an invisible intraventricular obstruction above the aqueduct and around the right foramen of Monro. The finding of normal ventricular fluid on ventriculostomy is not surprising, since the dilated ventricle from which the fluid was ' obtained is proximal to (i.e., upstream of) the hypothesized block. lntraoperative instillation of a nonionic contrast agent into the right lateral ventricle might have helped delineate the anatomical features of the hydrocephalus.
The finding of granulomatous pachvmehingitis with relative sparing of the leptomeninges in this case allows me to focus on a smaller differential diagnosis of chronic meningitis. That finding, along with the normal appearance and flow-cytometric features of the lymphocytes in the cerebrospinal fluid, dissuade me from strongly considering neoplastic meningeal seeding, which may appear as a pachymeningitis on MRI.2 This case highlights the excellent diagnostic results obtained when meningeal biopsies are performed in regions showing enhancement with gadolinium on MRI scans.3
Tuberculous meningitis is a primary consideration in any patient with granulomatous meningitis, pulmonary disease, and a positive tuberculin test. The disorder follows bacillemia, which originates either in a primary tubercular lesion or in one that is reactivated in association with aging, immunosuppression, or human immunodeficiency virus infection. The characteristic features of active tuberculosis may not accompany the meningitis, and chest radiographs are normal in over half of affected adults. The typical pattern of mononuclear pleocytosis with elevated protein and reduced glucose levels is found in only a minority of patients; as in this case, the protein level is less than 100 mg per deciliter, and the glucose level is more than 45 mg per deciliter (2.5 mmol per liter) in a quarter to a third of infected adults. Hyponatremia due to inappropriate secretion of antidiuretic hormones is found in some but not all patients. Smears and cultures of cerebrospinal fluid have a low sensitivity for identifying the tubercle bacillus, but the sensitivity can be increased to more than 80 percent by meticulous attention to technique, including the collection of multiple specimens of 10 to 15 ml and examination of up to 500 high-power fields. Since this type of examination requires about 30 minutes, the laboratory must be informed that the diagnosis is being considered. In this case, cultures were still negative on the 17th hospital day, but this is not surprising, since Mycobacterium tuberculosis takes about 20 times as long to generate as most other bacteria, and detectable growth in culture may take up to 8 weeks. A promising new tests based on immunologic techniques and the polymerase chain reaction offer hope for more rapid confirmation.
Several features of this patient's illness, however, raise serious doubts about the diagnosis of tuberculosis. The duration of symptoms for eight months is not characteristic of tuberculous meningitis. The median duration of symptoms before presentation ranges from two to four weeks and rarely exceeds a few months; untreated patients usually die within eight weeks. The absence of fever is also atypical. Fever occurs at some time during the course of the illness in more than 80 percent of patients, and in some series, fever is more frequent than an alteration of consciousness. Although hydrocephalus is the most common neuroradiologic abnormality, it is usually the communicating type, and other findings, such as tuberculomas and infarcts in the distribution of the medial striae and thalamoperforate arteries, are often present. Leptomeningeal enhancement of the basal cisterns is the usual pattern, and a hypertrophic pachymeningitis is rare. The erythrocyte sedimentation rate varies but is often only slightly elevated this patient's level is unexpectedly high, especiallv in view of the normal chest film. Finally, there was no evidence of upper-lobe cavitation or endobronchial disease on the CT scan of the chest. The combination of these atypical findings leads me to consider alternative diagnoses.
Other infections can cause granulomatous meningitis. Although nontuberculous mycobacteria usually infect patients with chronic lung disorders or depressed cellular immunity, disease caused by M. avium complex can occur in apparently normal persons and can occasionally cause meningitis. Such patients, however, characteristically present with a productive cough and abnormal chest films. The deep mycoses may cause a meningoencephalitis associated with a mild, resolving, or asymptomatic pulmonary infection. The most common type of fungal meningitis is cryptococcal, even in immunocompetent patients, but the test for serum cryptococcal antigen, which has a sensitivity of at least 90 percent, was negative in this case. Coccidioidomycosis and histoplasmosis rarely disseminate to the nervous system. Blastomycosis generally infects the brain and meninges late in the course of advanced disease. Aspergillus, mucor, and Pseudallescheria boydii are not usually found in immunocompetent persons. Among bacteria, brucella can cause a chronic granulomatous meningitis, but it is typically associated with fever, constitutional symptoms, and a history of exposure to infected animal tissues or products. Finally, the spirochetes Treponema pallidum and Barrelia burgdorferi may cause lesions that are predominantly or even entirely meningeal, but infection with either of these organisms would not explain the findings on the CT scan of the chest. Also, the negative serologic tests of cerebrospinal fluid and serum provide no diagnostic support, although their sensitivities are not optimal.
Neurologic involvement occurs in 5 percent of patients with sarcoidosis and is the presenting manifestation in about half these patients. Findings include cranial neuropathies and occasionally pachymeningitis. Nevertheless, it would be unusual for hydrocephalus and aseptic meningitis to be the sole manifestations of neurosarcoidosis. Also, only 10 to 15 percent of patients present with pulmonary infiltrates in the absence of lymphadenopathy. Finally, this patient's relatively advanced age, extremely high erythrocyte sedimentation rate, and normal angiotensin-converting–enzvme level in association with an active pulmonary process make the diagnosis of sarcoidosis unlikely.
Wegener's granulomatosis is a serious consideration in this case. A median interval of 15 months from the onset of symptoms to diagnosis has been reported. Although over 90 percent of patients have some type of airway disease, the initial manifestation of the disorder may not occur in the nose, sinuses, or lungs. Abnormalities on radiographs of the chest include infiltrates, nodules, and hemorrhages, reflecting the complex underlying pathological lesions characterized by necrosis, granulomas composed of palisading histiocvtes, and vasculitis. In about a third of cases, the pulmonary lesions detected radiographically are asymptomatic. The erythrocyte sedimentation rate is almost always markedly elevated, and hvpergammaglobulinemia may be present. The discovery that antineutrophil cytoplasmic antibodies (ANCA) are present in patients with Wegener's granulomatosis has led to early diagnosis of the disease and improved monitoring of its progression and treatment. An immunofluorescent pattern of diffuse cytoplasmic staining (c-ANCA) has a sensitivity of at least 90 percent and a specificity approaching 99 percent for diagnosing generalized Wegener's granulomatosis. An enzyme-linked immunosorbent assay has demonstrated the presence of an antibody that in most cases is directed against a 29-kd serine proteinase (proteinase 3). This immunologic reaction may contribute to the pathogenesis of the disease by inducing neutrophil degranulation.
complications of Wegener's granulomatosis occur in 20 to 50 percent of
cases, although they are not usually the initial signs of the illness.
Mechanisms of nervous system involvement include invasion from contiguous
structures, independent formation of intracranial granulomas, and
In addition to Wegener's granulomatosis, however, several other immune-related granulomatous disorders that involve the central nervous system should be considered. Isolated granulomatous angiitis is manifested as an acute or subacute multifocal encephalopathy and affects small parenchymal and leptomeningeal vessels; extracranial vasculitis is unusual, and the erythrocyte sedimentation rate is often normal. Forms of systemic necrotizing vasculitis that involve the nervous system include polyarteritis nodosa and the Churg–Strauss syndrome. Neurologic manifestations of polyarteritis nodosa occur late in the course of systemic disease, and asthma and hypereosinophilia are defining features of the Churg–Strauss syndrome. Peripheral neuropathy is the most common neurologic complication in both disorders. Lvmphomatoid granulomatosis is a rare disease of the lungs and skin characterized by angiocentric and angiodestructive infiltrates of atvpical lymphocytes and plasma cells, which sometimes progress to full-blown lymphoma. Cranial neuropathies and necrotic mass lesions in the cortex or brain stem occur in about 25 percent of cases of lymphomatoid granulomatosis and may be initial features. However, severe respiratory insufficiency and abnormalities on chest radiographs are characteristic of this disorder, the erythrocyte sedimentation rate is usually normal or only slightly elevated, and neither giant cells nor discrete palisading granulomas are seen. Rheumatoid disease may cause a meningoencephalopathy, with vasculitis and rheumatoid nodules typically found in the dura, but this complication usually occurs in patients with a positive test for rheumatoid factor and clinically established rheumatoid arthritis. Thus, none of these disorders fit the clinical picture in this case.
Idiopathic hypertrophic cranial pachymeningis is a rare disorder characterized on neuroimaging by evidence of thickening and enhancement of the dura, especially of the tentorium and falx. It is typically a chronic disease and is manifested most often by headache, ataxia, and cranial-nerve palsies. Dural granulomas are seen in 10 percent of cases. I could find only one case in which the patient was tested for ANCA, and the results were negative. It would be premature to make the diagnosis of idiopathic hypertrophic cranial pachvmeningitis in this case, and it would not explain the pulmonary findings.
Tuberculous meningitis is the diagnosis I would have been anxious not to overlook, and in view of the patient's age and her altered mental status on admission, I would have initiated antituberculous therapy immediately while looking for conclusive evidence of this or an alternative diagnosis. Empirical antituberculous therapy does not compromise the yield of positive cerebrospinal fluid smears or cultures if specimens are collected within the first week of treatment.
Nevertheless, for the reasons I have outlined, I believe Wegener's granulomatosis is the correct diagnosis, and the next diagnostic procedure should have been an ANCA test on the serum, with the hope of avoiding a lung biopsy. It is important to confirm this diagnosis, since prompt treatment with prednisone and cyclophosphamide results in marked improvement or partial remission in over 90 percent of cases .
Tuberculosis or Wegener's granulomatosis.
DR. JOHN SHMIDT'S DIAGNOSIS Wegener's granulomatosis.
DR. JOHN L. NIMS: The diagnostic procedure was serologic testing for ANCA. Indirect immunofluorescence testing revealed a perinuclear pattern of staining (p-ANCA). An enzyme-linked immunosorbent assay for antibodies to the neutrophil cytoplasmic protein myeloperoxidase was positive at a titer of 128 U per milliliter (normal value, less than 2.8). A test for antibodies to the neutrophil cytoplasmic protein proteinase 3 was negative. Antibodies to proteinase 3 or myeloperoxidase are highly specific markers for the spectrum of diseases with vasculitis that includes Wegener's granulomatosis, microscopical polyangiitis, the Churg–Strauss syndrome, and primary necrotizing and crescentic glomerulonephritis.38-40 The biopsy findings, together with the presence of antimyeloperoxidase antibodies, arc diagnostic of Wegener's granulomatosis.
Several assays for the detection of ANCA have been described. Indirect immunofluorescence testing is performed by staining neutrophils for the presence of one of two patterns: c-ANCA or p-ANCA. Antigen-specific immunoassays for the detection of antibodies to proteinase 3 and myeloperoxidase are performed with the use of immunofluorescence. The c-ANCA pattern of staining is closely correlated with the presence of antibodies to proteinase Antibodies to myeloperoxidase are among several auto-antibodies that produce the p-ANCA pattern. Only the findings of c-ANCA due to antibodies to proteinase 3 and p-ANCA due to antibodies to mveloperoxidase are specific for a spectrum of vasculitic syndromes that I have mentioned.}'-h3
These syndromes have long been known to be related. When there is renal involvement, it is generally in the form of a pauci-immune necrotizing crescentic glomerulonephritis. Wegener's granulomatosis has been described as a variant of polyarteritis nodosa; the Churg–Strauss syndrome has been considered a variant of Wegener's granulomatosis, and pauci-immune necrotizing and crescentic glomerulonephritis limited to the kidneys has even been called "renal-limited Wegener's granulomatosis." The clinical and histologic features of these syndromes overlap, and the features in an individual patient may evolve from those characteristic of one syndrome into those characteristic of another. Although earlier studies suggested that Wegener's granulomatosis is specifically correlated with the presence of antibodies to proteinase 3,44,45 more recent reports have indicated that some patients with Wegener's granulomatosis have antimyeloperoxidase antibodies.
The sensitivity of ANCA tests for diagnosing this spectrum of diseases is more than 90 percent when systemic disease is present,41 but when the disease is localized and no renal involvement is evident, the sensitivity is lower. The specificity of ANCA testing depends on how the assays are performed. Antigen-specific immunoassays performed together with immunofluorescence testing appear to provide the best results. With the techniques used at this hospital, the specificity of the assays has been more than 99 percent and even higher when the titer of antibodies to proteinase 3 or myeloperoxidase is high, as in this case.
The positive predictive value of ANCA assays also depends on the prevalence or prior probability of disease in the group of patients being tested. The pretest probability of Wegener's granulomatosis in this case was at least moderate, if not high. Even a pretest probability of only 10 percent, if combined with the high ANCA titer, would yield a predictive value of more than 97 percent. Together with the granulomatous features of the dural-biopsy specimen and the absence of the discrete tubercle-like granulomas that are characteristic of tuberculosis or sarcoidosis, the findings were considered diagnostic of Wegener's granulomatosis.
DR. MICHAEL A. PANZER: The patient was initially treated presumptively for tuberculosis with isoniazid and three other drugs while we continued the diagnostic workup. Once the ANCA titer was reported to be positive, the patient received intravenous methvlprednisolone as well as cyclophosphamide. Treatment with isoniazid was continued because of the positive tuberculin test. She was eventually discharged to a rehabilitation hospital while receiving prednisone and cyclophosphamide, and her condition has subsequently continued to improve. She is now ambulatory and living independently at a level of functioning very close to her premorbid level.
The ANCA titer fell to 46 LT per milliliter after the initiation of treatment.
DR. SHMIDT: The pulmonary ground-glass opacities were initially considered to be indicative of pulmonary edema. In the setting of Wegener's granulomatosis, however, they probably reflected hemorrhage. The calcified mediastinal nodes and calcified splenic and hepatic granulomas are consistent with the possibility of an earlier case of tuberculosis.
Wegener's granulomatosis with pachmeningertl granulornatous inflammation.
TABLE 1. HEMATOLOGIC LABORATORYVALUES.`
ON 13TH ON 17TH
ON HOSPITAL HOSPITAL
VARIABLE ADMISSION DAY DAY
Hematocrit (96) 32.5 - 35.3
Mean corpuscular volume (¤ms) 79
Erythrocyte sedimentation rate 113
White-cell count (per mm') 6,800 8,000
Differential count (%)
Platelet count (per mm3) 296,000 311,000
Prorhrombin time Normal Normal
Partial-thromboplastin time Normal Normal
Iron-binding capacity (µg/dl) 1 29
Folic acid (ng/ml) 22.1*
Vitamin B12, Normal
'To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the value for folic acid to nano-moles per liter, multiply by 2.266.
*The normal value is less than 3 ng per milliliter (6.3 nmol per liter).
BLOOD CHEMICAL VALUES.*
*To convert the value for urea nitrogen to millimoles per liter, multiply by 0.357 To convert the value for magnesium to milliequivalents per liter, divide by 0.5. To convert the value for calcium to miLlimoles per liter, mul-tiply by 0.250. To convert the value for phosphorus to millimoles per liter,
TABLE 4. SEROLOGIC AND
IgG mg/dl) 2180*
Kappa Img/dl) 18101
Lambda iimg/dl 1 894;1-
Kappa lambda ratio Normal
Protein electrophoresis Normal pattern with moderate, diffuse increase in gamma globulin
Rheumatoid factor Negative
Antinuclear antibodies Negative
Urinary histoplasma antigen Negative
Cryptococcal antigen Negative
Antibodies to Borrclia Negative
Antibodies to brucella species Negative
*The normal range is 614 to 1295 mg per deciliter. 1The normal range is 574 to 1275 mg per deciliter. I.The normal range is 269 to 638 mg per deciliter.