CHAPTER 96 NEUROSARCOIDOSIS AND NEURO-BEHÇET’S DISEASE
NEUROSARCOIDOSIS
Neurosarcoidosis is a localized manifestation of sarcoidosis involving the central nervous system (CNS) or peripheral nervous system (PNS). Sarcoidosis, a multisystemic granulomatous inflammatory disorder of unknown cause, is manifested frequently as a pulmonary and lymph node disease that typically appears in young adults between 20 and 40 years of age. Neurosarcoidosis may occur in 5% to 10% of patients with sarcoidosis as part of multiorgan disease involvement or as the first localized manifestation of the disease.1 The pathological hallmark of sarcoidosis is the presence of noncaseating granulomatous tissue reactions and of inflammation dominated by macrophage activation, as well as mononuclear and lymphocytic infiltration. In the nervous system, noncaseating granulomas and inflammation may occur in any compartment of the CNS or PNS, producing focal or multifocal tissue damage that leads to neurological dysfunction.
Epidemiology and Etiopathogenesis
The prevalence of sarcoidosis varies among different populations worldwide. In the United States, it appears to be more common in African Americans and white persons of northern European descent. In addition, foci of increased frequency of sarcoidosis have been described in some European countries. In developing countries in Latin America, Africa, and Asia, the prevalence of sarcoidosis remains uncertain because the high incidence of infectious granulomatous disorders such as tuberculosis, which closely resembles sarcoidosis, predominates as a clinical diagnosis. A multicenter case-control study of etiological factors in 736 patients with newly diagnosed sarcoidosis in the United States1 revealed neurological involvement in 4.6% of the patients. Interestingly, this study also revealed that women were more likely than men to have neurosarcoidosis and ocular involvement of the disease. The factors causing neurological involvement are still unknown, and it is still unclear whether racial or genetic factors play a role in determining the presence of CNS or PNS involvement.
The etiological factors involved in the pathogenesis of sarcoidosis remain elusive, but several hypotheses have suggested a potential role of infection, exposure to environmental factors, and noninfectious factors. The occurrence of geographical clusters and the increased risk among first- and second-degree relatives of patients with sarcoidosis are indicative of a role for an environmental or infectious etiological factor.2 Mycobacterium tuberculosis, Propionibacterium acnes, and Propionibacterium granulosum infections have emerged as potential agents in polymerase chain reaction studies of tissue biopsy specimens from patients with sarcoidosis; however, definitive studies to demonstrate a definite role for these or other infective agents have not been carried out.3 Genetic susceptibility, as determined by varying effects of several genes, has been proposed as an important factor determining the presence and variability of the clinical profile of sarcoidosis in different ethnic populations.4 Some major histocompatibility complex (MHC) alleles have been found to confer susceptibility to sarcoidosis (human leukocyte antigen [HLA]–DR11, -DR12, -DR14, -DR15, and -DR17) whereas others appear to be protective (HLA-DR1, HLA-DR4, and possibly HLA-DQ*0202). Polymorphisms in the angiotensin-converting enzyme, tumor necrosis factor α (TNF-α) and vascular endothelial growth factor genes have also been postulated to be associated with the disease in some population-based studies.5,6
Clinical Features
The clinical manifestations of neurosarcoidosis are heterogeneous, as noncaseating granulomas and inflammation may affect any compartment of the CNS and PNS (Table 96-1). The most frequent manifestations of neurosarcoidosis are associated with cranial neuropathy and the meningeal and encephalitic forms of the disease; clinical manifestations may overlap and produce complex neurological symptoms. The clinical course of neurosarcoidosis is variable and may exhibit a temporal profile consistent with a monophasic, relapsing-remitting, or chronic pattern. The extent of the CNS or PNS involvement and the evolution of clinical problems determine the magnitude of the patient’s neurological disability. Some of the acute manifestations of neurosarcoidosis, such as cranial neuropathies, have a monophasic pattern that resolve quickly with steroid treatment; others, such as the meningeal, encephalitic, and myelopathic forms, frequently have a subacute course that may evolve into relapsing-remitting or chronic forms of the disease, necessitating more aggressive treatment approaches.
TABLE 96-1 Clinical Variants of Neurosarcoidosis
| Clinical Forms | Neurological Manifestation | Clinical Profile |
|---|---|---|
| Meningeal form | Aseptic meningitis | Headaches |
| Basal meningitis | Increase intracranial pressure | |
| Chronic meningitis | Hydrocephalus | |
| Pachymeningitis | Single or multiple cranial nerve palsies | |
| Dural tumor-like sarcoid lesions | ||
| Cranial neuropathy form | Facial paralysis | Single or multiple cranial nerve palsies |
| Optic neuropathy | Bilateral Bell’s palsy | |
| Multiple cranial neuropathies | Diplopia | |
| Visual blurriness | ||
| Vestibular symptoms | ||
| Encephalitic form | Focal encephalitis | Headaches |
| Focal or multifocal leukoencephalitis | Psychosis | |
| Tumor-like sarcoid lesions | Seizures | |
| Focal neurological symptoms | ||
| Increased intracranial pressure | ||
| Neuroendocrine form | Panhypopituitarism | Diabetes insipidus |
| Hypogonadism | ||
| Hypothyroidism | ||
| Myelopathic form | Subacute or progressive myelopathy | Gait disturbances |
| Paraparesis/paraplegia | ||
| Bladder dysfunction | ||
| Paresthesias/dysesthesias | ||
| Sensory level disturbances | ||
| Neuropathic form | Multiple mononeuropathies | Multifocal or localized dysesthesias, paresthesias, weakness, monoradiculoneuropathies or polyradiculoneuropathies |
| Polyradiculoneuropathies | ||
| Myopathic form | Focal myositis | Weakness, muscle pain |
| Polymyositis |
Meningeal Forms
Basal meningitis, chronic meningitis, and pachymeningitis are frequent manifestations among the meningeal forms of neurosarcoidosis (Fig. 96-1). A careful clinical assessment and contrast-enhanced magnetic brain imaging (MRI) studies, as well as a complete examination of the cerebrospinal fluid (CSF), are necessary to rule out the presence of other diseases that frequently involve the basal meningeal compartment, including tuberculous and fungal or neoplastic meningitis. Because the basal region of the brain is one of the areas most commonly affected by meningeal forms, cranial nerve palsies and hydrocephalus are the most frequent clinical manifestations of these forms of neurosarcoidosis. In patients with meningeal forms of neurosarcoidosis, granulomatous inflammatory reactions may impair the reabsortion of the CSF in the arachnoid villi and/or produce obstruction of CSF outflow. This accumulation of fluid leads to aggressive forms of hydrocephalus and increased intracranial pressure. Special precautions should be taken in patients with hydrocephalus associated with neurosarcoidosis, because lumbar puncture procedures may increase the risk of decompensation and cerebellar tonsillar herniation. Some of these patients may require ventriculostomy or ventriculoperitoneal shunts to avoid further complications from increased intracranial pressure, but the decision to use these neurosurgical approaches must be made carefully. Other variants of meningeal involvement in neurosarcoidosis include spinal arachnoiditis or dural tumor-like lesions that resemble meningiomas and produce focal symptoms in the intracranial or spinal compartments, with increased intracranial pressure or myelopathic symptoms, respectively. These tumor-like lesions are associated with extensive but localized noncaseating granulomatous and inflammatory reactions of the dura mater and respond well to medical treatment without the need for surgical resection, except in situations in which there is a marked mass effect or increased intracranial pressure.
Encephalitic Forms
Focal encephalitis, leukoencephalitis, and multifocal white matter involvement are aggressive forms of neurosarcoidosis, inasmuch as these manifestations are frequently associated with subacute, relapsing-remitting or chronic patterns (Fig. 96-2). Symptoms associated with encephalitic forms include seizures, headache, signs of increased intracranial pressure, psychosis, motor dysfunction, cognitive decline, and other focal neurological manifestations. Focal or multifocal leukoencephalitic forms of neurosarcoidosis may mimic the clinical and MRI features of multiple sclerosis and/or neoplastic lesions. Patients with suspected demyelinating diseases should be evaluated to rule out the presence of sarcoidosis before the definitive diagnosis of such disorders is established. Some of the focal encephalitic forms of neurosarcoidosis represent aggressive forms of parenchymal CNS disease that become refractory to conventional treatment with steroids and may necessitate aggressive immunosuppressive therapy.
Figure 96-2 T1-weighted brain magnetic resonance image (MRI) with gadolinium enhancement in a patient with an encephalitic form of neurosarcoidosis. The brain MRI changes raised concerns for a glioblastoma multiform, but a brain biopsy revealed typical features of granulomatous reactions and multinucleated giant cell formation (see Fig. 96-5).
Neuroendocrine Forms
Some patients with neurosarcoidosis exhibit a selective focal granulomatous meningeal inflammation of the infundibular, peri-infundibular, and suprasellar regions that may evolve into aggressive forms of hypothalamic dysfunction, focal encephalitis, and/or hypophysitis (Fig. 96-3). These localized manifestations of neurosarcoidosis manifest clinically with a variety of hormonal deficiencies but frequently with hypogonadism, central diabetes insipidus, and panhypopituitarism. In patients with this form of neuroendocrine involvement, the granulomatous inflammatory activity is often monophasic and subacute but produces important long-standing endocrine problems that necessitate life-long hormonal replacement and careful endocrinological follow-up.
Myelopathic Forms
Although not as common as other forms of neurosarcoidosis, myelopathic forms may represent a diagnostic challenge if there is no previous history of systemic sarcoidosis. Myelopathic forms are frequently manifested as subacute or slowly progressive myelopathies associated with both motor and sensory symptoms. A presumptive or possible diagnosis of sarcoid myelopathy may be established if the patient has a previous history of systemic sarcoidosis, clinical evidence of myelopathy documented by clinical findings, and MRI findings of focal or multifocal intra-axial spinal cord lesions (Fig. 96-4). Because involvement of the spinal cord is frequently associated with slowly progressing tumor-like lesions, the diagnosis of sarcoid myelopathy is occasionally established after spinal cord biopsies are performed in patients with suspected spinal cord tumors.
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