Sarcoidosis is a multisystem granulomatous disorder. Its precise etiology is unknown, but there is evidence that it is caused by heightened immune processes at the sites of disease activity.49 Sarcoidosis can be thought of as an inflammatory response to an unidentified foreign antigen.49-54 The central pathologic hallmark of sarcoidosis, the granuloma (see figure), consists of macrophages, macrophage-derived epithelioid cells, and multinucleated giant cells that secrete cytokines. Around this central core exist CD4 and CD8 lymphocytes, B lymphocytes, plasma cells, and fibroblasts. The lymphocytes are thought to be stimulated by antigen presentation by activated macrophages present at sites of inflammation.55-60
Right: Photomicrograph at 400 magnification of a sarcoid granuloma in the brain, demonstrating a multinucleated giant cell.
Right: Photomicrograph at 400 magnification of a sarcoid granuloma in the brain, demonstrating a multinucleated giant cell.
In reaction to an antigen, monocytes and macrophages form granulomas. Ultimately, irreversible obliterative fibrosis can develop. Furthermore, small foci of ischemic necrosis can be found, probably because of vascular compromise due to perivascular inflammation. Importantly, these granulomas are not specific for sarcoidosis. Indistinguishable or nearly identical lesions occur in a variety of other conditions that must be excluded before a diagnosis of sarcoidosis can be made with certainty.
Sarcoidosis usually presents between the ages of 20 and 40 years but it also occurs in children and older populations. Clinical manifestations appear similar in all age groups. Intrathoracic structures are most commonly affected, followed by lymph node, skin, and ocular disease:
Frequency of organ involvement in sarcoidosis
Anatomic presence of the disease in any organ is possible and often occurs without overt clinical evidence of dysfunction. Sarcoidosis can present with constitutional symptoms and pulmonary or extrapulmonary manifestations, or it may be asymptomatic. It is estimated that 20-40% of patients are asymptomatic at presentation, with their disease being discovered by routine chest radiography.50
Neurologic symptoms are the presenting feature of sarcoidosis in one-half of individuals with neurosarcoidosis.42,43 One-third to one-half of neurosarcoidosis patients develop more than one neurologic manifestation of their disease:
Only rarely do patients with neurosarcoidosis have no evidence of disease in other organ systems, such as the lung.42,44-47,61,62 Systemic disease may not always be evident early in a patient's clinical course, however.
Because of its varied manifestations, neurosarcoidosis is in the differential diagnosis of many unexplained neurologic syndromes. The diagnosis of sarcoidosis is most secure when based on pathology and when more than one organ system can be documented to be involved. Because tissue from the nervous system is difficult to secure for pathologic analysis and other tests are not diagnostic of neurosarcoidosis, however, the diagnosis must sometimes remain tentative.
Palsy of the facial nerve (cranial nerve VII) is the single most frequent neurologic manifestation of sarcoidosis. It develops in 25-50% of all patients with neurosarcoidosis. Although usually unilateral, bilateral facial palsy also can occur, presenting with either simultaneous or sequential paralysis. More than half of all patients with facial palsy also have other forms of nervous system involvement. In general, the prognosis for the facial palsy is good, with more than 80% of patients having a good recovery of function.42,47
Hydrocephalus, affecting about 10% of neurosarcoidosis patients, is a potentially lethal complication. Patients with acute hydrocephalus may die suddenly from increased intracranial pressure, and even patients with chronic hydrocephalus have the potential to acutely decompensate. Patients with acute hydrocephalus characteristically present with headache, altered mentation or , and impaired gait. On examination, papilledema or other signs of raised intracranial pressure can be found. Acute decompensating hydrocephalus is a medical emergency that requires prompt diagnosis and treatment.
Parenchymal brain disease is reported in about half of patients with neurosarcoidosis. It can present in several forms. The most common is hypothalamic dysfunction. This usually involves the neuroendocrinologic system or "vegetative functions." Neuroendocrinologic disease in sarcoidosis can also be secondary to pituitary disease. Any of the neuroendocrinologic systems can be affected by sarcoidosis.42 Potential endocrinologic manifestations of neurosarcoidosis include thyroid disorders, disorders of cortisol , and sexual dysfunction. An elevated serum prolactin level, found in 3-32% of patients with sarcoidosis, may be an indication of hypothalamic dysfunction.
Hypothalamic disorders that affect vegetative functions vary considerably. A disorder of thirst is the most common hypothalamic disorder related to neurosarcoidosis and is attributed to a change in the hypothalamic "osmostat." More rarely, the of inappropriate secretion of antidiuretic hormone (SIADH) can occur.43,63 These hypothalamic disorders can lead to severe hyponatremia, which can cause seizures. Neurosarcoidosis-induced disruptions of hypothalamic function also have been described as causing disorders of appetite, libido, temperature control, weight regulation, and sleep.43,63
Intraparenchymal mass lesions due to sarcoidosis may present as an isolated mass (see figure) or masses occurring in any cerebral area or multiple cerebral nodules. Subdural plaquelike masses may mimic meningiomas. Calcifications may also be seen. In the past, intraparenchymal mass lesions were considered rare, but and have shown them to be more frequent than previously thought.
The diffuse encephalopathy and vasculopathy associated with neurosarcoidosis are not well understood. Moreover, it is often difficult, both clinically and pathologically, to separate these entities clearly and they frequently coexist. For these reasons, they can be considered as a single overlapping entity, but one form or the other may predominate in an individual patient.42 Figure 3 shows an example of the MRI changes in a patient with neurosarcoid encephalopathy.
Seizures are an important manifestation of CNS parenchymal disease due to neurosarcoidosis, and their significance has recently been better understood.48 They have been reported in up to 20% of patients with neurosarcoidosis and may be focal or generalized. Seizures in neurosarcoidosis have been correlated with a poor prognosis. 64 The poor prognosis of neurosarcoidosis patients with seizures is due not to the seizures themselves but rather to the fact that seizures are an indicator for the presence of severe CNS parenchymal disease or hydrocephalus. This more severe pathology produces a higher risk for progressive or recurrent disease or death.48,64
Diagnosis of neurosarcoidosis
Patients without documented systemic sarcoidosis
When a patient without documented systemic sarcoidosis develops a clinical syndrome suggestive of neurosarcoidosis, confirming evidence for sarcoidosis should be sought in other organ systems. Such systemic disease can best be documented when a thorough, systematic evaluation based on the known natural history of sarcoidosis is undertaken (see first table above). Because sarcoidosis most frequently affects intrathoracic structures, followed by lymph node, skin, and ocular disease, histologic support for a diagnosis of sarcoidosis should be pursued in those areas, following leads obtained from the patient's clinical evaluation.
Pulmonary involvement is so common in sarcoidosis that this should be the first organ system to consider when attempting to establish the presence of systemic sarcoidosis. Indeed, nearly 90% of patients with sarcoidosis are reported to show radiographic evidence of pulmonary involvement.65 Although an abnormal chest x-ray can be supportive evidence for the diagnosis of sarcoidosis, however, it is not necessarily specific or pathognomonic for sarcoidosis. Additional evidence to support pulmonary involvement can be obtained from pulmonary function testing, including diffusion capacity. When chest x-rays or pulmonary function studies suggest pulmonary involvement, a diagnosis of sarcoidosis is confirmed by obtaining histologic evidence of sarcoidosis with a transbronchial biopsy. To better define the extent of lung or lymph node involvement, chest CT imaging also can be useful.
A diagnosis of sarcoidosis is most secure when it is based on histologic confirmation, but on average, 30% lack histologic confirmation, and the diagnosis is often based solely on clinical and radiologic findings.50
Active sarcoidosis may cause an elevation in serum angiotensin-converting enzyme (SACE), which can then serve as a marker of the disease.51 Although it is the most specific laboratory test associated with sarcoidosis, SACE is not highly sensitive; just 50-60% of active sarcoidosis patients show abnormalities. Nor is it very specific; it is also often elevated in patients with other conditions, such as liver disease, diabetes mellitus, hyperthyroidism, systemic infection, malignancy, and .51,66
Patients with documented systemic sarcoidosis
Patients with well-documented systemic sarcoidosis who develop neurologic disease suspected to be neurosarcoidosis merit careful appraisal to exclude other causes for their neurologic problems. Neurosarcoidosis can be confused with many other neurologic diseases, and because it is often not possible or judicious to biopsy affected tissue from the nervous system to confirm neurosarcoidosis, good clinical judgment becomes critical.
In particular, sarcoidosis and seizures are relatively common disorders, and, therefore, sarcoidosis should not always be presumed as the cause of seizures in a patient with both disorders — their coexistence may be merely incidental. In general, patients with sarcoidosis who develop neurologic problems deserve consideration of disease entities that may mimic neurosarcoidosis, particularly infection and neoplasia.
Although not specifically diagnostic, there are tests that can support a presumptive diagnosis of neurosarcoidosis. Brain-imaging studies can be particularly helpful to confirm the presence, classify the nature, and monitor the treatment of neurosarcoidosis. The preferred imaging technique is now MRI with contrast enhancement.67 T2-weighted images are most useful, showing areas of increased signal intensity, especially in the periventricular distribution. Contrast administration helps by demonstrating leptomeningeal enhancement (Figure 4) as well as parenchymal abnormalities (see Figures 2 and 3). Enhancement presumably reflects a breakdown of the blood-brain barrier and implies active inflammation.
Spinal fluid analysis is another useful method for assessment, diagnosis, and staging of neurosarcoidosis. More than 50% of patients with CNS sarcoidosis have some cerebrospinal fluid (CSF) abnormality.42 CSF angiotensin-converting enzyme (ACE) activity tends to be raised in some 50% of untreated patients with CNS sarcoidosis,68 although abnormalities are also seen in the presence of infection and malignancy. The CSF-ACE level may be abnormal even with steroid therapy but less consistently than in untreated patients. The degree of elevation of CSF ACE may parallel the clinical course.68-70 A normal CSF-ACE assay does not exclude the diagnosis of neurosarcoidosis, however, and the diagnostic value of CSF ACE is limited by the lack of well-standardized assay methodology and normative values.
Treatment of neurosarcoidosis
Principles of treatment
No rigorous studies have compared various treatments for neurosarcoidosis. Most experts agree that corticosteroid therapy is the mainstay of treatment and is indicated for any patient without a specific contraindication to it. The patient's clinical course, expected natural history or prognosis, and adverse treatment effects or side effects should guide decisions about issues such as the optimal therapeutic dose and duration of therapy. A treatment paradigm is given in Figure 5.
Treatment alternatives to corticosteroids must sometimes be considered for patients with neurosarcoidosis. Indications for the use of alternate treatments include contraindications to corticosteroids as initial therapy, serious adverse chronic corticosteroid effects, and progressive disease activity in spite of aggressive corticosteroid therapy. Experience with alternatives is limited. There is not a single established alternative treatment, but several medications have been used:43,71
One nondrug treatment that has also been reported to have some limited success is radiation therapy.71,72
Practically, consideration should be given to introducing alternative therapy whenever a patient shows signs of serious corticosteroid side effects or requires frequent large increases in corticosteroid dosage to control symptoms. Treatment with an immunosuppressive agent or radiation is a logical adjunctive therapy for refractory neurosarcoidosis, given what is understood of the immunopathogenic mechanisms of the disease. Alternative therapy may allow a gradual decrease in corticosteroid dosage to prevent or minimize corticosteroid complications, often without deterioration in clinical status. Rarely, however, can corticosteroids be eliminated.
Recent series describe promising results with methotrexate to treat patients with refractory sarcoidosis or those who could not tolerate the side effects of corticosteroids.73,74 The same group reports good results treating neurosarcoidosis patients with methotrexate.75 In that series, many patients who failed treatment with methotrexate were then treated with intravenous cyclophosphamide. Although these reported results of methotrexate are promising and deserve consideration, the observations are based on nonrandomized and uncontrolled trials.
Treating patients with seizures
Seizures in patients with neurosarcoidosis are usually relatively easy to control, if the underlying CNS inflammatory process can be effectively treated.48 Once the sarcoid inflammatory disorder is adequately controlled with anti-inflammatory or immunosuppressive therapy, consideration can be given to reducing or even discontinuing antiepileptic medications.
If seizures recur, emphasis should be placed on assessing and treating the underlying inflammatory disorder rather than just focusing on antiepileptic drugs. Seizures have been shown to be an indication of the presence of parenchymatous involvement of the brain, which is in itself a very serious manifestation of neurosarcoidosis.47,48 Consequently, it is important to recognize the clinical relevance of seizures in patients with neurosarcoidosis. Seizures are useful warning signs that a patient may have one of the more serious forms of neurosarcoidosis, such as an intracranial mass lesion.48
Prognosis for neurosarcoidosis
The clinical course and prognosis for neurosarcoidosis varies but is somewhat predictable. Two-thirds of patients have a monophasic neurologic illness. These patients typically have an isolated cranial neuropathy, most often involving the facial nerve, or an episode of aseptic meningitis. The other patients have a chronically progressive or remitting-relapsing course. Those with a chronic course usually have CNS parenchymal disease, hydrocephalus, multiple cranial neuropathies (especially involving the second and eighth cranial nerves), peripheral neuropathy, or myopathy.47
The mortality of neurosarcoidosis overall is approximately 5-10%.42,43,47,48 As already discussed, sarcoidosis patients with seizures have a higher risk of progressive disease, a poorer prognosis, and a higher mortality, because seizures are associated with a higher of parenchymal brain involvement,48 and such parenchymal disease or hydrocephalus correlates with the poorest prognosis and the greatest risk of death.48
Despite limitations in our understanding of the natural history of sarcoidosis, treatment with corticosteroids does seem to benefit many patients with neurosarcoidosis. Even more important, patients benefit most from a comprehensive approach to care based on an understanding of the full clinical spectrum of neurosarcoidosis, an appreciation of the whole range of treatment options, and the anticipation of complications such as those relating to corticosteroid treatment.
Adapted from: Seiden L and Krumholz A. Inflammatory noninfectious disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;135-154.
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