Benign angiopathy of the central nervous system: Cohort of 16 patients with clinical course and long-term followup

Authors


Abstract

Objective

Benign angiopathy of the central nervous system (BACNS) is a subset of primary angiitis of the central nervous system (PACNS) with favorable outcome, not requiring prolonged immunosuppression. We retrospectively studied the clinical characteristics and prospectively assessed long-term outcome in a cohort of BACNS patients.

Methods

Patients meeting the clinical description for BACNS, evaluated and treated by a single investigator, were included. Data on demographics, signs and symptoms, laboratory studies, neuroimaging, brain biopsy, treatment, and complications were recorded. The long-term assessment included a phone interview utilizing the Barthel index and a specifically designed cognitive index.

Results

Sixteen cases met the inclusion criteria. Mean age was 40 years (range 10–66 years) with female:male ratio of 4.3:1 and a mean followup period of 35 months (0–128 months). Headache was the most common presenting symptom, seen in 88% of the cases, followed by focal symptoms (63%), and diffuse symptoms (44%). All patients had highly abnormal cerebral angiography, and magnetic resonance imaging abnormalities were present in 77% (10 of 13). Severe cerebral spinal fluid (CSF) abnormalities were present in 1 patient (7%). All followup cerebral angiography showed marked improvement. Recovery was demonstrated in 94% of the patients, 6% relapsed, and there were no deaths. Of patients assessed by the Barthel index, 71% showed no disability and 29% had mild disability.

Conclusion

There is a PACNS subset characterized by acute presentation (most commonly headache), normal to mildly abnormal CSF findings, female predominance, and highly abnormal cerebral angiography (reversible after treatment), requiring less intensive treatment than has been traditionally used.

INTRODUCTION

Primary angiitis of the central nervous system (PACNS) is a relatively rare and poorly understood form of vasculitis limited by definition to the brain, the spinal cord, and their surrounding tissues. For the first several decades following its modern description in the early 1950s, PACNS was considered a relentless and largely untreatable disorder, with a granulomatous vasculitic histopathology and was most often diagnosed at postmortem examination (1). In 1983, there was a promising report of 4 cases of PACNS successfully treated with the combination of high-dose glucocorticoids and cyclophosphamide (2). One of these cases had been diagnosed by biopsy and 3 by cerebral angiography. Clinicians subsequently became more optimistic regarding the ability to make the diagnosis earlier. This impression was also facilitated by the increasing availability of neuroimaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), and cerebral angiography. Over time it became increasingly common for patients to be diagnosed with PACNS solely on angiographic grounds without supporting histopathology. This trend resulted in patients, diagnosed solely on the basis of abnormal angiograms, being treated with prolonged and intensive immunosuppressive regimens based on the supposition that cases diagnosed by angiographic findings were clinically equivalent to biopsy-proven PACNS.

In the early 1990s, we and others began to question whether cases of PACNS diagnosed solely by cerebral angiography were indeed equivalent to those diagnosed by antemortem biopsy (3, 4). It was suggested that within the spectrum of angiographically diagnosed PACNS there existed a subset of patients with a predictably more benign outcome. These patients exhibited distinctive clinical features and required a shorter and less intensive course of therapy. In 1992, we attempted to define such a subset based on a comparison of angiographically diagnosed cases with histologically confirmed cases culled largely from the literature. We proposed the name benign angiopathy of the central nervous system (BACNS) (3). No subsequent sizable series of BACNS patients, which included angiographic or clinical followup, has been reported. We now describe our experience including the clinical features, treatment, and long-term outcome of 16 cases fitting the clinical description of BACNS. We provide angiographic followup in 10 of these cases and propose that the pathogenetic basis of BACNS may be mediated by vasoconstrictive as opposed to vasculitic mechanisms.

PATIENTS AND METHODS

Patients were selected from the 18-year clinical experience of one author (LHC) at the Cleveland Clinic Foundation. All patients fulfilled the proposed criteria for PACNS by Calabrese and Mallek (5), which include 1) the presence of an acquired, otherwise unexplained, neurologic deficit, 2) the presence of either classic angiographic or histopathologic features of angiitis within the central nervous system (CNS), and 3) no evidence of systemic vasculitis or any condition that could elicit the angiographic or pathologic features. For the purpose of this study, PACNS patients were included if they additionally fulfilled the clinical description of BACNS. These include an acute onset of headache and/or neurologic deficit, mild CSF findings, and a high probability angiogram for CNS vasculitis. CNS vasculitis is defined by involvement of at least one major branch of anterior and posterior carotid arteries or subbranches with areas of stenosis and dilatation similar to that seen in Figure 1 (i.e., vascular beading or alternating areas of stenosis and ectasia in multiple cerebral vessels) (6).

Figure 1.

Cerebral angiography of patient 12 at diagnosis (left) and after 1 month of therapy (right). Note the multiple areas of stenosis and dilatation in multiple vessels of the M2 branch of the middle cerebral artery and their resolution after treatment.

All charts of patients with BACNS were retrospectively reviewed and pertinent data extracted, including patient demographics, presenting and cumulative signs and symptoms, laboratory studies, neuroimaging data (CT scan, MRI, magnetic resonance angiography [MRA], cerebral angiography), CSF analysis, and brain biopsy results. Details on treatment, followup periods, relapses, and complications were also documented.

Assessment of patients' outcome included short- and long-term evaluation. The short-term outcome was that determined by the clinical status recorded at the last visit. This was classified as total recovery, recovery with residual neurologic dysfunction, deterioration, or death. Long-term outcome was determined prospectively by standardized phone interview after obtaining informed consent. Phone assessment utilized 2 instruments, including the Barthel index (7) and a newly described cognitive index designed for this study. The Barthel index is a standardized outcome measure tool used primarily to assess poststroke morbidity. It has been validated by Korner-Bitensky et al (8) for use over the phone. Questions explore activities such as eating, grooming, and toileting, as well as mobility. Scores range from 0 to 100% with higher scores signifying better outcome. A score of 100% indicates no disability; a score of 81%–99% indicates mild disability; 61%–80%, moderate disability; and 60% or less, severe disability. The cognitive index was developed specifically to assess psychocognitive function and headache status, as both are common findings in the PACNS patient population (Appendix A). Five different questions addressing memory, concentration, behavior, energy level, and persistence of headache (if it was present at diagnosis) constitute this index. Answers for each item were classified into 1 of 3 categories: major, minor, or no problem. Treatment was nonstandardized and evolved over the 18-year period of accruement.

RESULTS

Demographics and clinical features.

Summary of the demographic characteristics of the 16 patients, their clinical findings, and their mode of diagnosis is displayed in Table 1. Patients were generally young, with a mean age at diagnosis of 40 years (10–66 years). Females were predominant, with a female:male ratio of 4.3:1. Clinical onset was acute in most, with a mean period from onset of symptoms to diagnosis of 25 days (0–155 days). Headache was the most common symptom at presentation, reported in 88% (14 of 16) of the cases, followed by focal symptoms in 63% (10 of 16). Stroke represented 43% of the focal symptoms, followed by seizure (21%), visual disturbance (e.g., blurring, diplopia) (14%), ataxia (14%), and speech abnormality (7%). Changes in cognition or consciousness, which we defined as diffuse symptoms, were present in 44% (7of 16) of the patients. Constitutional symptoms, such as fever, weight loss, or fatigue were present in a single patient. Followup period was prolonged in most of the patients, with a mean of 35 months and a range of 0–128 months.

Table 1. Characteristics of the patients*
  • *

    CSF = cerebrospinal fluid; MRI = magnetic resonance imaging; WBC = white blood cell count.

  • Protein > 70 mg/dl or WBC > 10/mm3.

  • 14 total patients.

  • §

    13 total patients.

  • 2 total patients.

Demographics and clinical symptoms 
 Number of patients16
 Mean age, years (range)40 (10–66)
 Female/male, n13/3
 Mean prodrome, days (range)25 (0–155)
 Mean followup, months (range)35 (0–128)
 Headache, n (%)14 (88)
 Focal symptoms, n (%)10 (63)
 Diffuse symptoms, n (%)7 (44)
 Constitutional symptoms, n (%)1 (6)
Diagnostic studies 
 Severe CSF abnormality, n (%)1 (7)
 Abnormal MRI, n (%)10 (77)§
 Positive brain biopsy, n (%)0 (0)
 Positive cerebral angiography, n (%)16 (100)

Angiography, MRI, and pathology results.

Cerebral angiography was performed in all patients. All the 16 initial studies demonstrated a high probability for vasculitis, previously defined as alternating areas of stenosis and/or ectasia or vascular beading in more than 1 vascular bed (6). Eighty-one percent (13 of 16) of the patients underwent MRI of the brain at initial presentation. Those who did not have MRI had either CT done at presentation or MRI done at a later time. Of the 13 MRI examinations, 77% (10 of 13) were abnormal. Abnormal findings included white matter signal changes in 23% (3 of 13), infarction in 31% (4 of 13), subarachnoid hemorrhage in 8% (1 of 13), and localized intracranial hemorrhage in 15% (2 of 13). Table 2 summarizes the neuroimaging results in all patients. Only 2 patients (12%) had brain biopsy performed, and those showed no pathologic findings.

Table 2. Details of neuroimaging, CSF findings, treatment, outcome and followup periods of all patients*
Patient numberCTMRIAngioFollowup Angio/MRATiming of followup AngioCSF protein, mg/dlCSF WBC, cells/mm3SteroidsCytotoxicsCa blockOutcomeFollowup period, months
  • *

    CT = computed tomography of the head; MRI = magnetic resonance imaging of the head; MRA = magnetic resonance angiography; Angio = cerebral angiography; NL = normal; NA = not applicable; NR = not reported; NO = not done; WM = white matter; Hem = hemorrhage; IC = internal capsule; SAH = subarachnoid hemorrhage; MS = multiple sclerosis; HP = High probability angiography (i.e., areas of stenosis and dilatation in multiple vessel territories); CSF = cerebrospinal fluid; WBC = white blood cells; RR = recovery with residual; TR = total recovery; Ca block = calcium channel blockers.

  • Initial cytoxan pulse then orally for 10 months before our evaluation.

  • Six pulses of cytoxan before our evaluation.

  • §

    Imuran for 3 months before our evaluation.

1NLNOHPNONANONONoneNoneYesRRNo F/U
2NLNLHPNONA453<6 monthsNoneYesTR12
3NLInfarctHPNONA431<6 monthsNoneYesRRNo F/U
4SAH↑ Signal WMHPImproved38 days671<6 monthsNoneNoneRelapse43
5NOInfarctHPImproved18 daysNLNL<6 monthsNoneYesRR58
6NLInfarctHPNL3.5 monthsNL0<6 monthsNoneYesTR16
7NO↑ Signal WMHPNONANR6NoneNoneYesTR118
8InfarctInfarctHPNONA453<6 monthsNoneYesRR63
9HemHemHPImproved3.4 monthsNLNL<6 monthsNoneYesTR6
10NONLHPNL MRA2.5 months531<6 monthsNoneYesTR2.4
11Edema in ICNOHPNONA224NoneNoneNoneTR60
12NL↑ Signal WMHPNL28 days277<6 monthsNoneYesRR1
13SAHSAHHPNL3 monthsNONO<6 monthsNoneYesTR3
14NONOHPImproved8 months54NL>6 monthsYesYesRR128
15NLNLHPImproved27 days350>6 monthsYesYesTR44
16HemHem/MSHPNL5 months41018<6 monthsYes§YesRR5

Followup angiography.

Not all patients underwent repeat cerebral angiography. From early on in the experience, it was not known or expected that presumed vasculitic changes were reversible. Over the 18-year clinical experience, the clinical course began to suggest that in some patients the underlying lesions could represent a reversible form of angiopathy, and angiographic followup at shorter and shorter time intervals was included in the standard evaluation and treatment plan. Sixty-three percent (10 of 16) of the patients had repeated cerebral angiogram or MRA following a mean period of 3 months (minimum 18 days, maximum 8 months) from the initial study. Nine patients had followup cerebral angiography and 1 patient had a repeat MRA (initial MRA done at diagnosis; Table 2). All patients demonstrated marked improvement in the previously described intracranial vessel abnormalities. Figure 1 shows cerebral angiographic findings of patient 12 at diagnosis and their resolution 1 month later.

Cerebrospinal fluid results.

Eighty-eight percent (14 of 16) of the patients had CSF analysis at time of diagnosis. Median CSF protein was 39 mg/dl and median CSF white blood cell count was 1.5 cells/mm3. Seventy-nine percent of the patients undergoing lumbar puncture had normal CSF white blood cell counts; 2 patients had mild elevation of CSF white blood cell count (6 and 7 cells/mm3). One patient (case 16) had a CSF white blood cell count of 18 cells/ mm3 and elevated CSF protein of 410 mg/dl. Nine patients (69%) had normal CSF protein levels; 3 patients had mild elevation of CSF protein (54, 57, and 67 mg/dl). Case 16 had concomitant multiple sclerosis and intracranial hemorrhage. The elevated CSF protein was felt to be accounted for by her initial diagnosis of multiple sclerosis and the corrected white blood cell to the number of red blood cells was normal (Table 2).

Associated conditions and/or factors.

Table 3 summarizes potentially confounding conditions in that they are known to be associated with angiographic abnormalities similar to those detected in our patients. Three patients had the onset of neurologic symptoms after exposure to sympathomimetic medications, including 2 with phenylpropanolamine use and 1 with pseudoephedrine. One patient experienced the headache 4 days postpartum without any evidence of preeclampsia or eclampsia. Two patients presented in association with subarachnoid bleed; 1 patient undergoing angiography 4 days after the onset of symptoms, and the second 5 days after the onset of symptoms. Intracranial hemorrhage was observed in 2 patients, with 1 patient undergoing angiography 5 days after the onset of symptoms and the other patient undergoing angiography 10 days after the symptoms. While it is possibile that these vascular changes could be due to blood in the subarachnoid space, the pattern observed in these patients of diffuse narrowing of distal small arteries contrasts with the more typical finding in patients with subarachnoid bleeds where the major cerebral arteries at the base of the brain are primarily involved, with distal branch sparing. Two patients developed their symptoms in the settings of complex headaches, both of which were described as exertional in nature.

Table 3. Associated conditions or factors in patients with benign angiopathy of the central nervous system
Condition or factorNo. of patientsRemarks
Postpartum14 days after delivery
Subarachnoid hemorrhage2Angiography done 4 days after symptoms
Intracranial hemorrhage2Angiography done 5 days after symptoms
Sympathomimetic drugs3Phenylpropanolamine, pseudoephedrine
Complex headaches2Exertional headache

Treatment and complications.

Treatment.

No standard protocol was employed. Table 2 displays the details of treatment, the outcomes at last visit, and followup periods in the cohort. The treatment strategy varied depending on clinical features of the individual patient. In every case following our assessment, no patient required glucocorticoids for more than 6 months and no patient received a cytotoxic medication. Ten patients (77%) were treated with tapering short-term glucocorticoid therapy, starting with high doses (i.e., 1 mg/kg/day or greater of prednisone) for a duration of less than 6 months. The 3 other patients (23%) received no glucocorticoids at all. Two were treated solely with calcium channel blockers and 1 received no therapy. Each of these latter 3 patients experienced complete remissions and had no relapse after a mean followup period of 59 months (range 1–118 months). Calcium channel blockers were used in 11 of the 13 (85%) patients with or without glucocorticoids. Three of the total 16 cases were treated with high-dose cytotoxic agents before their evaluation at our institution. In each of these cases, treatment was discontinued based on the presumptive diagnosis of BACNS.

Case 14 was a 29-year-old man who experienced the sudden onset of the “worst headache of his life” and was found to have a mild elevation of CSF protein (54 mg/dl) with a normal CSF white blood cell count and a high probability cerebral angiogram. The patient was aggressively treated with high-dose glucocorticoids, initially 60 mg, and cyclophosphamide. Eight months after initial therapy, a repeat angiogram had markedly improved, but his headaches persisted despite being on 20 mg of glucocorticoids and 200 mg of oral cyclophosphamide at the time of our evaluation. A repeat lumbar puncture showed a normal CSF protein and white blood cell count. Based on this normal CSF finding along with the marked improvement in the cerebral angiogram, we recommended discontinuing cyclophosphamide, tapering glucocorticoids, and adding a calcium channel blocker. These treatment changes were associated with total recovery and successful management of his headaches.

Case 15 was a 43-year-old woman who developed the worst headache of her life but was initially found to have a normal MRI and CSF examination. The symptoms persisted and 2 weeks later she experienced a localized intracerebral bleed and was subsequently found to have a high probability cerebral angiogram for vasculitis. The patient was treated with prolonged high-dose glucocorticoids and monthly intravenous cyclophosphamide for a total of 6 months. She improved but developed numerous complications, including multiple areas of avascular necrosis of bone. Twenty-seven days following the first cerebral angiogram, a repeat angiogram was near normal and her glucocorticoids were tapered but not discontinued. Fourteen months later, following a total hip replacement, she experienced a recurrence of her severe headaches and was treated with escalating doses of glucocorticoids. It was noted in the anesthesia record that as a result of intraoperative hypotension she was treated with fluids and intravenous ephedrine. Her treating physicians, fearing a recurrence of her PACNS, recommended reinstitution of glucocorticoids and cyclophosphamide. Because of her concern about further toxicity, she was seen by us for another opinion. Following our evaluation, glucocorticoids were tapered and discontinued and her persistent headaches were successfully managed with calcium channel blockers alone.

Case 16 was a 43-year-old woman who experienced an acute onset of headache accompanied by evidence of localized intracerebral bleed and high probability cerebral angiography for arteritis. She was treated with high doses of glucocorticoids and a short course of oral cyclophosphamide followed by 3 months of azathioprine based on the presence of persistent headache. As part of our evaluation she underwent repeat cerebral angiography, which was dramatically improved. Immunosuppressive therapy was discontinued and the headaches were successfully managed with the addition of a calcium channel blocker.

Complications.

Five identified complications occurred in 3 patients (3 of 16). These included noninfectious esophagitis (2 patients), avascular necrosis (1 patient), osteoporosis (1 patient), and oral thrush (1 patient). Only 1 of the complications was major, avascular necrosis, and this occurred in patient 15, who was heavily treated with glucocorticoids before our evaluation.

Short- and long-term outcomes.

Short-term outcomes were generally favorable with 50% (8 of 16) of the patients experiencing total recovery and 44% (7 of 16) experiencing recovery with residual findings limited to minor headache; no patient had major neurologic sequelae. There was only 1 relapse (6%) after tapering therapy, and this patient was retreated with glucocorticoids alone, without addition of a cytotoxic agent, with good response. There were no deaths in this group.

Results of long-term outcome as measured by the Barthel index and the cognitive index are described in Table 4. Seven patients (56%) were available for followup for the telephone interview. Seventy-one percent of the interviewed patients showed no disability on the Barthel index, and 29% had only mild disability. None of the patients had major morbidity as assessed by the Barthel index. Patients generally performed as well on the cognitive index. Sixty percent of the answers were rated as “no problems,” 31% as “minor problem,” and 9% as “major problem.” New and persistent headaches were noted in only 29% (2 of 7) of the patients who completed the interview.

Table 4. Results of Barthel and cognitive indices
Barthel indexCognitive index
DisabilityPercentage (n) of patientsSymptomsPercentage (n) of answers
None (score of 100%)71 (5/7)None60 (21/35)
Mild–moderate (score of 61%–99%)29 (2/7)Minor problem31 (11/35)
Severe disability (score of ≤60%)0 (0/7)Major problem9 (3/35)

DISCUSSION

PACNS has been viewed by some authors as a homogeneous and progressive disorder with fatal outcome unless treated vigorously with a combination of glucocorticoids and immunosuppressive drugs, most frequently cyclophosphamide (2). In 1993 we questioned whether there existed within the PACNS spectrum a “benign” subset that could be treated with less intense therapy (9). The clinical features of this benign subset included the acute onset of headache with or without a focal neurologic deficit, female predominance, normal or near normal CSF findings, and the presence of a high probability or classic angiogram for vasculitis. The term BACNS (benign angiopathy of the central nervous system) was proposed based on the monophasic and often benign clinical course relative to patients with pathologically documented granulomatous angiitis of the central nervous system (9). The term “angiopathy” was incorporated to suggest that the pathologic mechanism of this disorder could possibly be other than inflammatory and, in particular, could represent a reversible vasoconstrictive disease or vasospasm.

Until recently, the only support for this concept was a limited number of anecdotal case reports of PACNS with similar clinical descriptions with benign outcome (10, 11) and several analyses based on retrospective reviews of the PACNS literature documenting differential clinical and laboratory features between patients diagnosed on purely angiographic versus pathologic bases (3, 4, 9, 12). Angiographically defined patients were more likely to be female with acute onset of presentation, along with mild to normal CSF findings and with a better outcome than the pathologically defined patients. In addition to these observations, Call and colleagues (12) reported on a small but important series of 4 patients who shared similar clinical features to BACNS cases; these authors, however, proposed the etiology to be that of a reversible segmental vasoconstrictive disorder. Despite these rare reports and inferences based on retrospective reviews of the literature, there have been no sizable series of such cases reported with any significant followup and outcome data. We now report a cohort of 16 patients fulfilling the clinical description of BACNS and include angiographic followup, treatment, and long-term clinical outcome in the majority of patients.

The seminal features of our series include its female predominance (female:male ratio of 4.3:1), acute onset with a mean duration of symptoms to diagnosis of 3.5 weeks, benign CSF analysis, and florid angiographic findings. Furthermore, these features contrast sharply with patients with true granulomatous angiitis of the central nervous system who usually present with chronic onset of the disease (mean duration of symptoms to diagnosis of 454 days), highly abnormal CSF, and female:male ratio of 4:3 (13).

The angiographic findings in our series were nearly always bilateral, associated with multiple areas of smooth, symmetric narrowing, often with post stenotic dilatation, and with a distribution that tended to involve smaller rather than the larger vessels at the base of the brain. These contrast with the findings in subarachnoid bleeding, which are generally limited to the large vessels at the base of the brain.

Treatment was nonstandardized and evolved over time as more calcium channel blockers and a shorter duration of glucocorticoids were employed. Ten patients were treated with 6 months or less of glucocorticoids, with or without supplemental calcium channel blockers. Two patients were treated with calcium channel blockers alone, and a single patient received no therapy at all. Three additional patients were initially treated with aggressive therapy prior to their evaluation at our institution and subsequently had their therapy discontinued. Later cases in the series were also treated with the addition of a calcium channel blocker, most often verapamil, in an initial dose of 240 mg/day or higher if needed to control symptoms, most often, headache. In general, for patients presenting with the most typical BACNS symptoms, we recommend instituting high-dose prednisone at a dosage of 1 mg/kg/day along with calcium channel blockers. In those cases presenting with stroke and intracranial hemorrhage, more aggressive therapy with pulse glucocorticoids may be warranted. Following the resolution of acute illness, glucocorticoids can slowly be tapered over 6 to 12 weeks depending on the clinical response, at which time followup angiography should be done. If patients respond clinically and angiographically, we continue calcium channel blockers long term.

If patients fail to show any significant degree of angiographic resolution or progression, we believe the diagnosis is strongly in doubt. Further diagnostic considerations should be given immediately with the most likely mimics being cerebrovascular atherosclerosis, emboli, or a hypercoaguable state. Intravascular neoplasms, as well as other rare acquired vascular diseases, should also be considered. Lastly, it is possible that failure to improve may result from a more aggressive form of vasculitis for which glucocorticoids alone are insufficient therapy. In our experience, however, this last possibility is extremely rare.

Headache was the initial symptom in the majority of patients and was often described by the subjects as the worst headache of their life. It was interesting to note that the headaches frequently responded to glucocorticoids alone; however, they often required the addition of a calcium channel blocker for complete relief. Several patients (patients 14, 15, and 16) remained symptomatic with headache despite prolonged use of immunosuppressive drugs and only improved with the addition of a calcium channel blocker. Two patients in this series improved with calcium channel blockers alone and 1 patient resolved spontaneously. Our results indicate that patients with BACNS may need less aggressive and shorter therapy duration than previously thought. Most of our patients recovered after short-term treatment of glucocorticoids, not exceeding 6 months duration, without the addition of cytotoxic drugs. Furthermore, patients who were initially treated with cytotoxic medications before our evaluation improved with the addition of calcium channel blockers despite the discontinuation of their immunosuppressive therapy, indicating a possible vasoconstrictive pathology in these cases.

Angiographic followup was performed in 10 patients and demonstrated marked improvement in all cases. The time of followup angiography varied in our series and represents our generated experience over time. Patients seen earlier in this experience were not subjected to repeat angiogram for many months, but later it became apparent that more prompt angiographic resolution often occurred. Now it is our standard practice in such patients to repeat cerebral angiography between 4 and 6 weeks after the initial study. We feel that this is particularly important because the improvement of the angiographic abnormalities serves not only to assist in monitoring therapy and tapering medications, but also in securing the diagnosis. As noted above, failure to see dynamic change upon repeat angiography in our opinion has strong negative predictive value for the diagnosis of BACNS and either suggests refractory PACNS or, more likely, an alternative diagnosis.

Little is known about the angiographic followup of biopsy-proven cases. Alhalabi and Moore (14) studied the serial angiographic changes in patients with PACNS. Resolution of angiographic findings in their series depended on the timing of treatment and the vessel size. When treatment was initiated early on, many areas of segmental narrowing returned to normal appearance. Small arterial vessel occlusions reopened, but not those of medium-sized arteries. However, it is not clear whether all these patients were biopsy-proven cases or not (14).

Our study is the first to report long-term followup using a validated scale (i.e., Barthel index) (7) as well as a new scale developed expressly for this investigation (cognitive index; Appendix A). Not unexpectedly, the group did quite well, with the vast majority of patients showing no evidence of residual neurologic deficits or only mild degrees of impairment. No patient demonstrated severe disability as long-term sequelae of their illness. These data are in contrast to patients not falling within the BACNS subset of PACNS requiring more extensive immunosuppressive therapy who have less favorable outcome, in whom only 42% showed no disability on the Barthel index compared with 71% of the BACNS patients (13).

The etiology of the vascular disease in this cohort is unclear, but could be the result of true arteritis or, alternatively, a reversible vasoconstriction or vasospasm. Although definitive proof is lacking for either, we strongly favor the latter based upon several lines of reasoning. First, our case series closely resembles, clinically and angiographically, similar case studies that have been reported in association with other disorders linked to reversible vasoconstriction. These include vasculopathy in the postpartum period (15–18), vasculopathy associated with pheochromocytoma (19), and that associated with the use of sympathomimetic drugs (20–32). In each of these examples, the clinical picture is characterized by similar angiographic findings, benign spinal fluid, and a monophasic course. Furthermore, particularly in cases of sympathomimetic drugs, cerebral hemorrhage is not common. In addition, similar angiographic changes have been rarely reported in patients with complex headaches (4). These headaches have most often been referred to as exertional headaches or sex headaches, because they come on during or following exertion. In several of our patients, a history of exertional headaches could be elicited and 1 patient experienced the onset of this disorder in the postpartum period. Three other patients had some proximate exposure to sympathomimetic drugs, though it is unclear what role, if any, these played in the development of their cerebrovascular disease.

Finally, although we have demonstrated that the BACNS subset of PACNS demonstrates distinct clinical features, we cannot imply that these are diagnostic criteria. Validation of diagnostic criteria requires large numbers of patients both with and without the disease to better define specificity and predictive value. We are well aware that not all patients presenting with the same clinical and angiographic picture have such a benign outcome (33) and we do not believe that all patients should be immediately classified as having BACNS. We now propose the inclusion of improvement of angiographic abnormalities on followup between 6 and 12 weeks as an additional criterion to ensure the reversible nature of this syndrome. In the absence of angiographic improvement, the diagnosis should be questioned and the patient reevaluated.

Acknowledgements

The authors wish to acknowledge the Ayhan Sahenk Foundation for their research support at the Vasculitis Care and Research Center, Cleveland Clinic Foundation.

APPENDIX A

Table  . COGNITIVE AND BEHAVIORAL EVALUATION*
  • *

    PACNS = primary angiitis of the central nervous system.

Energy: How is your energy level?
 Major problem: I spent most of the time in bed
 Minor problem: I have to stop and rest during the day
 No problem: Normal
Memory: Do you have any problem with memory?
 Major forgetfulness (forgetting your address, name, phone number)
 Minor forgetfulness
 No problems
Concentration: Do you have any problem with concentration?
 Major reduction in general comprehension (e.g., lost work)
 Minor inability to think with accustomed clarity
 None
Mood/behavior: Have you had any change in your mood/ behavior?
 Major problem: Suicidal ideation or attempts
 Minor problem: Depression or irritability
 No problems: None
Headache: Since you have been treated for PACNS did you have any new headache?
 Major problem: Frequently >3 times/week
 Minor problem: Infrequent <3 times/week
 No problems: None

Ancillary