Investigations into neurosarcoidosis.
Imaging
CT scans are not sensitive enough to show up sarcoidosis in the brain, but Magnetic Resonance Imaging (MRI) on the other hand shows up lesions in the affected areas in the majority of cases.
Often the only abnormality detected on imaging is what is known as enhancement on scans following injection of a contrast agent. This shows up where the inflammation actually is within the brain and its lining. The imaging abnormalities are however by no means specific and are seen in infections such as bacterial and tuberculous meningitis, tumours and other inflammatory disorders.
Cerebrospinal fluid
We often perform lumbar punctures to measure the constituents if the spinal fluid. This can show raised protein and white blood cell levels as well as raised levels of chemicals which form part of the inflammatory process. These tests are helpful in trying to differentiate the disease from another such as a tumour.
There is evidence for blood brain barrier breakdown, as in other inflammatory conditions, but oligoclonal bands, which occur in multiple sclerosis, do not occur. CSF angiotensin converting enzyme (ACE) levels are raised in around 50% of patients with active neurosarcoidosis, but CSF ACE varies with CSF protein estimation and is known to be increased in a variety of other neurological diseases, including bacterial infections, multiple sclerosis and neurological Behçet’s syndrome. It may however be a useful marker of response to treatment. It is the same ACE level which is used to monitor progress when the lungs are involved.
Biopsy
We like to obtain what is called histological confirmation of sarcoidosis before starting treatment; it would be terrible to treat the wrong disease incorrectly, so we often take tissue samples at biopsy. When we biopsy the lungs or skin or liver it often involves a straightforward procedure with low risks. As noted above, we often biopsy the muscle as well, and this too has a low chance of side effects.
To biopsy the brain or the meninges is a major undertaking and although the risks involved are not high, we only perform such a biopsy if we cannot obtain histological confirmation of sarcoidosis from other tissues, or if we feel that there is a significant chance that the neurological condition is separate from sarcoidosis elsewhere. This is done by a neurosurgeon, often with modern image-guidance techniques.
Some patients develop neurological problems months or years after their sarcoidosis has been diagnosed. In others the disease may start with neurological symptoms; some are seen to have problems in other tissues but in others only the nervous system is involved. We do not currently understand why this may be. The value of screening for systemic sarcoidosis in patients with isolated neurological syndromes has not yet been identified. Isolated series show a relatively high incidence of sarcoidosis in such patients. A proportion of these may subsequently go on to develop systemic symptoms, and reports suggest that this may take place between months and up to five years after the onset of the neurological disorder, and another proportion show specific abnormalities with chest x-ray, Gallium scanning, pulmonary function tests, blind liver, skin and conjunctival biopsies in otherwise asymptomatic patients. Serum angiotensin converting enzyme (ACE) levels are raised in up to 88% of patients with active sarcoidosis and may be useful in monitoring response to treatment. It is said that the sensitivity of ACE measurement as a diagnostic tool for systemic sarcoidosis is increased to 99% if a Gallium scan shows appropriate abnormalities. However, Gallium scans frequently show isotope uptake in non-specific patterns.
Treatment
No formal placebo controlled blinded trial of treatment of neurosarcoidosis has been undertaken and case reports are limited to very small non-blinded, non-controlled prospective studies and retrospective reports. It is clear that use of corticosteroids is associated with an improvement of symptoms in the majority of cases in the acute phase of the disease, however many patients require high doses for prolonged periods of time.
Relapse may be associated with too rapid reduction in steroid dosage, or steroid cessation or to incomplete treatment by insufficiently high doses. High dose steroids over a long period of time necessitate the use of other immunosuppresive treatments and azathioprine, methotrexate, cyclosporin A, cyclophosphamide and chlorambucil have all been tried with varying reports of success.
Not all patients, however, seem to respond; one small study of 12 patients who failed to respond to prednisolone, and were treated with chloroquine or hydroxychloroquine showed that in a majority greater control of the disease was attained, enabling a reduction in steroid dosage. Radiotherapy to large hemisphere mass lesions, unresponsive to immunosuppresive treatment, has been associated with an improvement of symptoms in cases with short follow-up.
More recently mycophenylate, thalidomide, pentoxifylline and TNFa antagonists have been used in systemic sarcoidosis and in neurosarcoidosis.
At the Royal Free London our own preference is the use of moderate or high dose weekly methotrexate with folic acid, since this appears to work well with a lower side effect profile than other immunosuppressive drugs. The majority of our patients on this treatment improve or are stabilised in the long term. We are using TNFa antagonists such as infliximab and Adalimumab more and more when the response to treatment isn’t enough or when patients cannot tolerate the more common medications. We have used these drugs in about 30 of our 200 patients with neurosarcoidosis with an excellent response.
Course and prognosis
In two thirds of patients with neurological involvement, the illness is an acute, or subacute one associated with recovery and followed by a prolonged remission. The remaining third go on to develop further attacks and sometimes also a progressive deterioration. It seems that patients with spinal cord disease and mass lesions within the brain tend to have further attacks and the accrual of disability, whereas those with meningitis and cranial neuropathy tend to be associated with a more favourable prognosis.
An American study of 25 patients, reviewed after five years, showed that 17 (68%) had had a single illness, 8 (32%) had had a relapsing course, and none had had a progressive course. Relapse arose in 33% of patients seen in a Belgian series of patients. This is rather similar to that seen when sarcoidosis affects tissues outside the nervous system. In the medical literature it is suggested that involvement of the nervous system is a much more serious manifestation and that it is more likely to be fatal. Nowadays we feel that this is not the case provided that the disease is diagnosed quickly and treated vigorously with the best medications.