Sarcoidosis is a disorder of unknown cause which can affect almost any organ in the body; the lungs, eyes, skin and liver are the most frequently so. In many cases the disease is mild and self limiting: in others it may run a fatal course. The prevalence of sarcoidosis (how many people are affected by it) is 100 to 400 in every million people in American and Scandinavian series and about 250 per million in the UK.
The disease is caused by the development of inflammation within the tissues affected; this is characterised by the development of groups of inflammatory cells which come together to form clumps of tissue known as epithelioid granulomas in affected organs. These are the “Sarcoid granulomas”. The inflammation prevents that part of the affected tissue from working as it should, causes damage if left untreated for some time, and can lead to the laying of scar tissue which is irreparable.
For the majority of patients the disease is self-limiting, so it can go away on its own. This is common when it affects the lungs, lymph nodes and skin. These patients tend not to receive treatment. For others it may come and go – relapse and remit, and treatment is usually recommended. Treatment is always recommended and is essential for the patients whose disease is severe, affects many organs and does not settle down on its own.
Neurological complications arise in 5 - 10% of all cases of sarcoidosis, so is very rare, but sometimes the neurological problem can develop before the other signs of sarcoid develop, making it a very difficult disorder to diagnose.
This is the most common manifestation of the neurological complications of systemic sarcoidosis in which it arose in 73% of one series and in 60% in another. It tends not to be severe and recovery usually occurs. Facial neuropathy is the most common manifestation of this at a frequency of 12% - 64%. Frequently bilateral, the lesion may arise in the nerve within an enlarged parotid gland or at the skull base or brainstem.
Double vision due to ophthalmoloplegia (when the nerves which make the eyes move are affected) has been noted in several reports but is very rare as is isolated trigeminal neuropathy which causes facial numbness. The eighth cranial nerve may be involved in a number of ways; subacute unilateral hearing loss due to involvement of the nerve or the cochlea itself, and sometimes also the brain stem. This may or may not be associated with vertigo leading to a feeling of giddiness and imbalance. Lower cranial neuropathies also occur with involvement of the ninth, tenth and twelfth nerves leading to difficulty with speech and swallowing, but this is relatively less frequent than other cranial neuropathies.
Involvement of the optic nerve can lead to visual loss has been noted in some 5% of cases in which the nervous system is involved and can be due to pressure on the optic nerve by an inflammatory mass within the brain, to inflammation of the nerve itself or to inflammation within the eye (uveitis). Patients may present with a subacute painful reduction in vision indistinguishable on clinical grounds from optic neuritis, or with a progressive painless decline in vision, but it affects both eyes more commonly. In general the visual loss is worse than that which is seen in optic neuritis, but it also tends to improve with adequate treatment.
Involvement of the brain itself may arise either due to the development of inflammation of the lining of the brain spreading in or to a mass of inflammatory tissue forming within the brain. The former may present with psychiatric symptoms with abnormal mental states including psychosis. Others present with what is known as encephalopathy with a fluctuating level of consciousness and often the signs of the condition vary from day to day.
Focal mass lesions may cause weakness or numbness down one side, headaches are extremely common and epileptic seizures may also occur. These problems are often the most difficult to treat of all cases of neurosarcoidosis. Mass lesions may be mistaken for tumours, and sometimes doctors recommend an operation or biopsy to find out what the problem is due to before sarcoidosis is diagnosed. Involvement of the cerebellum and brain stem and the development of an akinetic rigid syndrome similar to Parkinsonism have been reported but are rare.
Hypothalmic and pituitary involvement
Autopsy series have shown that the development of inflammation in and around the hypothalamus, the pituitary gland and around the third ventricle is the most common site of neurological involvement. 10% - 35% in some series have symptoms related to disease in this region, so it may occur without causing obvious symptoms during life. The most common presenting symptom is of thirst and a need to drink more than usual. Obesity, sleep disturbance and temperature fluctuation have also been reported. Patients with lesions in this area may have visual field defects.
Meningitis and its complications
Acute meningitis is not common but a chronic and indolent basal granulomatous leptomeningitis or arachnoiditis is a common autopsy finding and may seemingly be asymptomatic or unrecognised. Cranial neuropathies may or may not occur and hydrocephalus may arise, in which the ventricles enlarge due to an increase in pressure around the brain, which may necessitate an operation to drain excess fluid from the brain. Treatment of this is often extremely difficult owing to shunt blockage.
The condition known as hypertrophic pachymeningitis can occur in Sarcoidosis and in other diseases like rheumatoid arthritis, and causes chronic headache, visual symptoms and hearing problems. These occur when the nerves passing out through the meninges become inflamed.
Spinal cord involvement
All parts of the spinal cord may be affected. Most commonly patients present with a cervical cord or conus medullaris involvement, which may be painful. The clinical syndrome varies between mild involvement with numbness, and severe, with evidence for transverse myelitis leading to difficulty walking and bladder problems. MRI scans show inflammation of the spinal cord and sometimes, like in the brain, it is thought to be a tumour before the diagnosis is made.
Involvement of the cauda equina has also been reported. This presents with an ascending, often bilateral, predominantly sensory disturbance with bladder and bowel problems. It tends not to be painful.
Neuropathy reflects involvement of the nerves underneath the skin and outside of the brain and spinal cord.
- A symmetrical neuropathy involving the nerves of sensation and muscle control progressing over months or years is most typical.
- A purely sensory neuropathy has also been described and mononeuritis multiplex, when lots of different nerves are affected, may also occur.
- A subacute radiculoneuropathy resembling Guillain Barré syndrome has also been noted, in which patients develop an ascending numbness and weakness which can sometimes become sufficiently severe to require hospitalisation. Involvement of this part of the nervous system may occur unnoticed without any symptoms.
- Granulomatous masses underneath the skin or around joints may cause compressive neuropathies such as carpal tunnel syndrome.
- Recently a severe painful neuropathy known as a small fibre neuropathy has been shown, and is often not quickly diagnosed.
Muscle involvement is frequently asymptomatic, and there are two forms:
- The nodular form involves the development of nodules of inflammation which may be single or multiple within limb muscles, sometimes associated with mild tenderness, but often not causing symptoms. Nodules are readily seen on MRI scans of the affected tissue and these lesions show contrast enhancement. Gallium scans often show uptake within the nodules.
- The myopathic form presents with a slowly progressive painful weakness and loss of muscle tissue in which MRI shows no nodules, but Gallium scans may show increased uptake. Muscle blood tests are sometimes elevated but are usually normal. Granulomas are seen on muscle biopsy, and response to treatment with immunosuppression and corticosteroids is poor, with the majority of patients continuing to deteriorate.
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.
Often lumbar punctures are performed to measure the constituents of 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.
The consultant usually obtains what is called histological confirmation of sarcoidosis before starting treatment; tissue samples are taken at biopsy to ensure the appropriate treatment is administered. A biopsy of the lungs or skin or liver often involves a straightforward procedure with low risks. As noted above, a biopsy of the muscle is taken as well, and this too has a low chance of side effects.
However, to biopsy the brain or the meninges is a major undertaking and although the risks involved are not high, such a biopsy is only performed if it is not possible to obtain histological confirmation of sarcoidosis from other tissues, or if 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. This is an area that requires further understanding. 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.
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 Hospital, the 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 immunosuppressives. The majority of patients on this treatment improve or are stabilised in the long term. The Royal Free Hospital uses TNFa antagonists such as infliximab under experimental conditions and the results so far are very encouraging. Recently other hospitals in the US and the UK have had similar good results. It seems likely that before long drugs such as these will be the treatment of first choice for patients who relapse or have progressive neurological disease.
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 x 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.
Is Neurosarcoidosis fatal?
Early reports suggested that once sarcoid got into the nervous system very little could be done about it, and frequently, because of this, a lack of understanding that the disease did affect the nervous system and a lack of treatment, it often was. Nowadays, however, it is clear that prompt early and vigorous treatment such as that outlined above, the prognosis for an improvement in the condition is now very good, and indeed many recover well. At the Royal Free Hospital, the specialist team has looked after over 100 patients with the disease and only two have died, neither directly related to the condition itself.
Can Neurosarcoidosis occur without evidence that Sarcoid has affected other tissues in the body?
Yes it can, and there are currently no clear reasons for this. It is likely to be related to the type of immune system the patient is born with and what the trigger is which sets off the disease; if it goes for the lungs then the lungs will be affected, and so on.
Is it like MS?
MS is another disease caused by inflammation within the nervous system but it is a very different disease and requires very different treatment. It is thus important for the neurologist to distinguish between the two diseases early on in order to select the best treatment. Like any disease, both MS and neurosarcoidosis can be mild or severe, with different treatments, prognoses and outcomes.