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Primary angiitis of the central nervous system
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Principle investigator: Dr Desmond Kidd


Consent form 
Consultee information sheet
Patient information sheet

Background:Primary angiitis of the central nervous system (PACNS) is a rare disorder which has been much under-researched and considerably misunderstood. The medical literature is predominately a rheumatological one (for the obvious reasons that Rheumatologists deal with vasculitis), but there are (by definition) no systemic features.

The prevalence is thought to be 0 5 – 1 per million, with a peak in middle age and rather more common in men than women.

Patients present with headache and neurological symptoms which often fluctuate day to day. Sudden deficits simulating stroke may arise, but more common the disorder is subacute with a gradual acquisition of neurological signs which worse and spread to other areas of the nervous system. Occasionally a slowly progressive disorder simulating dementia may arise, and more rarely still a mass lesion misconstrued as a brain tumour may be seen.

Nearly 30 years ago a series of diagnostic criteria was put forward and these have not been improved upon since. The authors put store in the then newly recognised angiographic feature of beading of the medium sized intracerebral vessels. This however is a very non-specific feature and is seen more commonly with a separate disorder known as reversible cerebral vasoconstriction syndrome, whose treatment and prognosis is entirely different to PACNS. It may also be seen in radiation induced cerebral vasculopathy and in association with various infections. Its specificity is too low to allow it to remain within the diagnostic criteria as they stand. 

A few case series have been published over the years, and even more recent ones have included patients who may well have alternative disorders. Yet others have included patients with entirely separate conditions such as auto-immune encephalitis.

The time has come, therefore, for the disease to be studied carefully both clinically and pathologically in order to define the natural history and clinical and imaging features, and in particular through immunopathological study, of the optimum treatment regimes. This is increasingly important with the advent of modern biological therapies which have the capability specifically to arrest various immune mechanisms, thereby allowing recovery and prevention of permanent neurological impairments.

We propose therefore a prospective study of PACNS throughout the entire United Kingdom. Patients will be invited to participate though their neurologists and rheumatologists through the NIHR clinical research network and the British neurological surveillance unit, and the vasculitis UK organisation. We anticipate gaining an understanding of the epidemiology of the disease throughout the whole of the UK and then studying the clinical and imaging features, the spinal fluid and blood investigation results, and finally and most importantly the neuropathological features.

Most patients will have had a brain biopsy since it is impossible to diagnose the disorder without one, and the small amounts of tissue which have been stored in paraffin blocks will be sent to us in order that we undertake an immunohistochemical evaluation. We would anticipate finding a series of different pathological appearances which would allow us to forecast the optimum treatment for each subsection of the disease.

Study protocol

The study will be run through the auspices of the NIHR clinical research network (CRN) and participating physicians will be able to pass on the information sheet and consent form to their patients. We will also target Neurologists specifically through the Association of British Neurologists’ Neurological Surveillance Unit in the same way. We will also advertise the project through social media and a website run through the Institute of Immunity and transplantation Neuroimmunology Unit at University College London, and finally though the Vasculitis UK organisation. We would hope thus to allow all patients diagnosed to be given the opportunity to consider to participate.

Those who consent will agree that their medical records, blood, spinal fluid and imaging investigation results (as well as the scans themselves) will be forwarded to the study team at the Royal Free Hospital.

The clinical features and investigation results will be analysed and stored in a pseudonymised manner according to data protection guidelines, the scans anonymised and copied then returned to the referring hospital.

The brain biopsy specimens will be sent from the referring neuropathology department to our own and stored under data protection guidelines within the Neuropathology department of the Royal Free Hospital. The paraffin blocks will be cut and stained in the following way:

Existing diagnostic slides will be reviewed, in particular the H&E, Nissl and Luxol fast blue sections and if available all previous immunohistochemical stains. Paraffin blocks will then be used and new stains applied in order to identify T cell type, B cells, plasma cells and macrophages, and complement, MHC class and immunoglobulins.

The identification of cell loss will be assessed using MAP2 and NeuN stained sections.

A quantitative analysis of cell density will be made using an ocular morphometric grid covering 1 mm2 at x100 magnification.

Dural, leptomeningeal, parenchymal tissues and arterioles and venules will all be examined thus and an assessment made of the site of involvement, its severity, its immunohistochemical features, and the neuropathological consequences.

All those who consent to participate would be asked to be approached at three monthly intervals to let the study team know their clinical state and their medication. The referring Physicians will be approached in the same way, in order that we may understand the response to treatment and a final clinical assessment a year after diagnosis. Patients would have the opportunity it they wished to ask that their clinical care be transferred to the Royal Free Hospital.

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