Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disorder of the blood vessels of the brain and the spinal cord without any evidence of systemic vasculitis. PACNS was first described as a distinct clinical entity in 1959, and since, multiple different clinical presentations have been reported. Clinical manifestations of PACNS at the time of diagnosis are non-specific with various presenting symptoms. A headache has been the most common presenting symptom in the majority of the PACNS cases. Other symptoms include focal neurological deficits including hemiparesis, aphasia, numbness, visual symptoms, ataxia, among others.
The exact etiology and pathogenesis of PACNS are unknown, but infectious agents such as varicella zoster virus (VZV) have been postulated as one of the triggers. Other proposed causes include the following:
Studies which describe the exact epidemiology of this rare disorder have not been done, and the only available data shows an annual incidence rate of 2.4 cases per 1 million person-years. The disorder has also been found to have an equal distribution among both the sexes and the median age of diagnosis of about 50 years.
Specific activation of the immune system and more specifically, T cells by various triggers are thought to cause the inflammation of blood vessels in the central nervous system leading to PACNS. Immunohistochemical staining of biopsy samples in PACNS showed an extensive infiltration around the small cerebral arteries by CD45R0+ T cells. Matrix metalloproteinases such as MMP-9 have been described as one of the prime effector molecules in animal models of PACNS.
Histopathology in PACNS shows small and medium vessel vasculitis affecting parenchymal and leptomeningeal arteries. Three different types of vasculitic patterns have been described in PACNS. These include granulomatous type, necrotizing type, and lymphocytic type. The most common type, granulomatous, shows numerous granulomas with multinucleated cells. The necrotizing type presents with fibrinoid necrosis similar, and lymphocytic type shows extensive lymphocytic inflammation with plasma cells.
The onset of PACNS is usually insidious, and the course is slowly progressive. Acute presentations have also been reported but are, however, less common. Symptoms of PACNS are non-specific, and multiple symptoms are usually present at the initial presentation. A headache is the most common presenting symptom; other common presenting symptoms include cognitive dysfunction and stroke. Overall, the presenting symptoms and signs from the most common to the least common include:
A combination of symptoms is usually present in most patients. PACNS should always be considered as a possibility in cases of rapidly progressive cognitive decline and personality changes of unknown etiology.
Diagnosis of PACNS is difficult due to the absence of a biomarker in the setting of a variety of non-specific presentations. Laboratory investigations like erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor, anti-neutrophil cytoplasm antibody (ANCA) are neither sensitive nor specific for the diagnosis of PACNS. The only useful laboratory investigation is cerebrospinal fluid (CSF) examination which shows an abnormality in more than 90% of the cases. A mild increase in the leukocyte count or total protein or both is seen in a majority of cases. Radiographic findings are quite useful in cases of PACNS, an abnormal MRI is seen in more than 90% of a case of PACNS, with ischemia being the most common abnormality noted.
The diagnostic criteria for PACNS formulated by Calabrese and Mallek are used for diagnosis, and a diagnosis is made if all of 3 diagnostic criteria are met. These include the presence of an unexplained acquired neurologic deficit after extensive investigation for other causes, the presence of evidence of an inflammatory arteritic process within the CNS by either angiography or histopathological examination or both; and no evidence of any other system vasculitis or any other disorders to which the angiographic or histopathologic features can be secondary.
Henceforth, the principal tools in the diagnosis of PACNS are conventional angiography and central nervous system biopsy. Abnormal findings noted in angiography include alternating segments of stenosis and normal or dilated segments and arterial occlusions. Magnetic resonance angiography (MRA) may be used in the diagnosis instead of conventional angiography. However, it has a lesser sensitivity compared to a conventional angiogram. CNS biopsy can also be used in the diagnosis of PACNS, however, the sensitivity of biopsy is lower and the specificity higher.
A diagnostic approach which combines the clinical, laboratory and radiologic findings with angiography and, if a required biopsy is most prudent.
The treatment strategies for primary CNS vasculitis are primarily derived from case reports and cohort studies. In most patients use of glucocorticoids alone or in combination with cyclophosphamide was shown to improve symptoms. The response rates for both monotherapy and combination therapy were found to be similar, around 80%. The general recommendation is to start oral prednisone therapy promptly at the time of diagnosis at an initial dose of 1 mg/kg per day. In nonresponsive cases, cyclophosphamide should be started promptly. The sufficient duration of therapy is 12 to 18 months in most patients. In patients with more severe presentations, 1 gm methylprednisone per day for three days along with cyclophosphamide can be used. However, the evidence of intravenous (IV) steroids being superior to oral regimen has not been noted. Pulses of IV methylprednisone can be given as required for disease flares.
In cases of PACNS resistant to both glucocorticoids and immunosuppressants, tumor necrosis factor-alpha blockers (infliximab, etanercept) and mycophenolate mofetil can be used to treat the disease. These should be used as adjunctive therapy along with the standard therapy. Prophylactic therapy against Pneumocystis jirovecii and osteoporosis should be given to all patients along with the standard therapy.
Serial MRI and MRA every 4 to 6 weeks after initiation of the treatment and then every 3 to 4 months during the first year along with thorough neurological examinations are indicated for monitoring the course of the illness.
When considering the possibility of a diagnosis of PACNS, it is important to rule out other conditions which can mimic PACNS. These mimicking conditions can be grouped as below
The first group is termed as reversible cerebral vasoconstriction syndromes (RCVS) which include Call-Fleming syndrome, migrainous vasospasm, and post-partum angiopathy. These conditions bear the closest resemblance to primary CNS angiitis. They can be differentiated by their acute onset and normal CSF findings. On further testing, even though angiography may be abnormal in these cases, a biopsy will never show vasculitic changes.
The second group of disorders which can mimic PACNS are secondary CNS vasculitis. This is a broad grouping which encompasses numerous infectious, rheumatic, autoinflammatory disorders along with other disorders which can secondarily cause CNS vasculitis. The infectious causes of secondary CNS vasculitis include bacterial (tuberculosis, syphilis), viral (Epstein-Barr virus, VZV), and fungal (Candida, Aspergillus). The rheumatic and autoinflammatory causes include Churg-Strauss disease, SLE, Behcet syndrome, among others. Other disorders which can cause CNS vasculitis include Moyamoya disease, fibromuscular dysplasia, and radiation vasculopathy. A complete workup for these secondary CNS vasculitides should also be made before confirming a diagnosis of PACNS.
Prognostic indicators from randomized control trials lack cases of PACNS. However, data obtained from retrospective observational studies show favorable outcomes when patients are treated with either glucocorticoids or a combination of glucocorticoids and cyclophosphamide. Some degree of reduction in life expectancy is observed in PACNS cases when compared to general population. Poor outcomes are found to be associated with larger vessel involvement.
Patients can have a prolonged clinical course lasting years, additional flares can result in worsening of neurological deficits. The recurrence rate in some studies is reported to be 27%. Prolonged steroid and use of other immunosuppressant medications for maintenance treatment is associated with significant side risk of hypertension, type 2 DM, and increased risk of opportunistic infections.
PACNS is a rare diagnosis and needs an interdisciplinary team approach including a rheumatologist, internist, endocrinologist, neurologist, radiologist, and pathologist. Patients on chronic steroid therapy should be closely followed for side effects associated with long term steroid use including hyperglycemia, osteoporosis, and increased risk of infections. The disease process can last for many years with intermittent flares or recurrence. Patients benefit from physical and occupational therapy for rehabilitation.
Patients must be advised about the potential chronicity of the disease process. Side effects and the need for close monitoring of medications like cyclophosphamide and steroids must be explained to them. Lifestyle modifications and aggressive treatment of underlying medical conditions like diabetes mellitus, hypertension, and osteoporosis must be pursued. Patients should be advised to take pneumocystis pneumonia prophylaxis if they are on long term steroid therapy. Frequent CBC monitoring on cyclophosphamide therapy is advised.
The diagnosis and management of PACNS is complex and best done with an interprofessional team that includes a rheumatologist, internist, endocrinologist, neurologist, radiologist, and pathologist. The cause in many cases is not known and empirical treatment with corticosteroids is the norm. When patients fail to respond, other potent immunosuppressive agents are added. The pharmacist and nurse should educate the patient on the potential adverse effects of drugs used to treat PACNS. Pharmacists should consult with the prescriber regarding any potential interactions, and verify dosing. Nursing can monitor treatment progress, and inform the team/chart any concerns. Even when patients respond, recovery is prolonged and may take months or a few years. These patients need continuous monitoring for several years until symptoms subside. Without long term studies, little is known about the long term outcome of these patients but relapses are common. (level V)
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