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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management
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Differential Diagnosis

The histologic differential diagnosis includes fungal and mycobacterial infections. These can usually be excluded using special stains. Special stains are also useful in excluding amyloid angiopathy with a granulomatous response. The presence of granulomas within the parenchyma and the rarity of blood vessels within the granulomas help distinguish sarcoidosis from primary angiitis of the CNS. As in all cases, the clinical history and presence of disease elsewhere are essential for making the correct diagnosis. Clinically, the most significant differential diagnoses of neurosarcoidosis include multiple sclerosis, CNS tuberculosis, neuromyelitis optica, transverse myelitis, HIV infection, and neuro-Behcet’s disease.

Diagnosis

Neuroimaging plays a crucial role in diagnosing of neurosarcoidosis, and all suspected patients should undergo magnetic resonance imaging of the brain and spinal cord with and without gadolinium contrast. Interestingly, many of neuroimaging abnormalities of neurosarcoidosis mimic other inflammatory, neoplastic, demyelinating, and

Extra-axial masses in sarcoidosis

Fig. 5.4 Extra-axial masses in sarcoidosis. (a, b) Axial T2- and enhanced axial T1-weighted images demonstrate an enhancing T2-hypointense extra-axial mass in the left cerebellopontine angle cistern (arrow). (c, d) Coronal T2 and enhanced coronal T1 images from a different patient show a T2-hypointense enhancing right tentorial mass (arrow). Noncontrast CT (not shown) did not demonstrate any calcification. Biopsy (not shown) revealed granulomatous inflammation (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

infectious neurological diseases. Also, the disease may manifest as meningeal involvement either as a focal thickening concerning for meningioma or diffuse pachymenin- geal involvement as seen in intracranial hypotension or leptomeningeal disease. Hydrocephalus, either communicating or noncommunicating, may develop as a result of severe meningeal inflammation. Various neuroimaging abnormalities of the neurosarcoidosis are presented in Figs. 5.4, 5.5, 5.6, 5.7, 5.8, and 5.9 [19].

Leptomeningeal involvement in sarcoidosis

Fig. 5.5 Leptomeningeal involvement in sarcoidosis. (a, b) Enhanced axial and coronal Tl-weighted images demonstrate nodular leptomeningeal enhancement in the basilar cisterns and posterior fossa. (c, d) Enhanced axial T1-weighted images in a different patient demonstrate nodular leptomeningeal enhancement along the cerebellar folia (arrows). Involvement of perivascular spaces is seen at a higher level in d (arrow) (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

The classification by Zajicek and colleagues [20] is by far the most acceptable and utilized diagnostic criteria for neurosarcoidosis (Table 5.1). As per them the disease process can be categorized as definite (direct neural tissue confirmation), probable (neurologic inflammation along with evidence of systemic sarcoidosis), and possible (typical clinical presentation but no other criteria met except for the exclusion of other potential etiologies).

In almost half of patients with neurosarcoidosis, intramedullary spinal cord lesions are present with involvement of >3 segments with a patchy and noncontiguous dissemination which may or may not enhance and is usually accompanied by

Cranial nerve enhancement in sarcoidosis

Fig. 5.6 Cranial nerve enhancement in sarcoidosis. (a, b) Axial fat-suppressed T1 images show enhancement of the left optic nerve (thin arrow). Lacrimal and parotid glands are enlarged (thick arrows in a and b, respectively). (c) Bilateral trigeminal nerve enhancement is seen in a different patient (arrows). (d) Enhancement of bilateral seventh to eighth nerve complexes is seen in another patient (arrows) (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

meningeal enhancement. In acute phase the affected spinal cord appears swollen and expanded, while chronic cases manifest with spinal cord atrophy. However, acute lesions may at times be nonenhancing as well.

Examination and analysis of cerebrospinal fluid (CSF) also assists clinicians to establish the correct diagnosis and exclude other differential diagnoses. The authors of this chapter routinely perform spinal tap on all patients suspected of having neurosarcoidosis. CSF examination of these patients reveals inflammatory features such as increased protein concentration (>200 mg/dL) and elevated white blood

Parenchymal lesion in sarcoidosis

Fig. 5.7 Parenchymal lesion in sarcoidosis. (a, b) Enhanced axial T1- and T2-weighted images at presentation demonstrate an enhancing T2-hypointense left frontal mass (arrow). There is surrounding nonenhancing T2-hyperintensity due to vasogenic edema. Also note thin dural enhancement overlying both frontal lobes. (c) Noncontrast CT scan obtained 1 year later shows worsening lesion size and edema (arrow). The patient had been on low-dose prednisone and was symptomatically stable. (d) MR image obtained following high-dose prednisone therapy shows a decrease in edema but only partial resolution of the enhancing left frontal mass (arrow). There was no further decrease in size of the mass on serial scans during the next 2 years with the patient on immunosuppressive therapy (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

cell count (mononuclear pleocytosis) [>50 cells pL] and the presence of oligoclonal bands along with elevated IgG indices. In some cases CSF glucose level is low. A normal CSF panel (which may be present in one-third of patients even in the presence of contrast-enhancing MR lesions or biopsy-proven neurosarcoidosis or in

Spinal cord involvement in sarcoidosis

Fig. 5.8 Spinal cord involvement in sarcoidosis. (a-c) Enhanced parasagittal and axial Tl-weighted images of the cervical cord show multiple enhancing parenchymal nodules (arrows). The peripheral distribution of these nodules, which are abutting the surface of the cord, suggests a leptomeningeal origin of these nodules. Note enhancement extending along the nerve roots (open arrow, c) (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

patients with isolated facial palsy) does not exclude such diagnosis. In all patients, the CSF examination should include search for malignant cells utilizing flow cytometry, serology for various infections, bacterial cultures, PCR assays for viral agents, and serologic studies for a number of infections. Angiotensin-converting enzyme (ACE), which is produced by granulomas, is increased in 24-55 % of patients, and while it is a nonsensitive marker of neurosarcoidosis, it is highly specific [19, 21].

Electromyography and nerve conduction studies enable clinicians to diagnose patients with neuromuscular diseases such as neuropathy, mononeuritis multiplex, and myopathy. This test also helps the neurophysiologist to determine whether the disease process is demyelinating versus axonal, how severe and widespread the neuropathic process is, and whether it is acute or chronic. Routine nerve conduction

Sellar-suprasellar involvement in sarcoidosis

Fig. 5.9 Sellar-suprasellar involvement in sarcoidosis. (a) Enhanced coronal T1-weighted image shows an enlarged and enhancing pituitary infundibulum (arrow). This patient also had multiple enhancing parenchymal nodules in a perivascular distribution. (b) Enhanced coronal T1-weighted image from a different patient shows a homogeneously enhancing infundibular and hypothalamic mass (arrow) (From Shah et al. [19]. Copyright permission obtained from American Society of Neuroradiology)

Table 5.1 Proposed diagnostic criteria for neurosarcoidosis

Definite

Clinical presentation suggestive of neurosarcoidosis with exclusion of other possible diagnoses and the presence of positive nervous system histology

Probable

Clinical syndrome suggestive histology of neurosarcoidosis with laboratory support for CNS inflammation (elevated levels of CAF protein and/or cells, the presence of oligoclonal bands, and/or MRI evidence compatible with neurosarcoidosis) and exclusion of alternative diagnoses together with evidence of systemic sarcoidosis (either through positive histology, including Kveim test, and/ or at least two indirect indicators from gallium scan, chest imaging and serum ACE)

Possible

Clinical presentation suggestive of neurosarcoidosis with exclusion of alternative diagnoses where the above criteria are not met

From Zajicek et al. [20] Copyright permission obtained

study with main concentration on large nerve fiber may miss a diagnosis of small fiber neuropathy. In cases where a systematic diagnosis approach fails to establish a diagnosis, the neurologist should consider muscle and nerve biopsy. In such cases the presence of epineural and perineural granulomas and granulomatous vasculitis may indicate a diagnosis of neurosarcoidosis. Accurate diagnosis of small fiber neuropathy is necessary since it causes disabling problems such as cardiac sympathetic denervation, periodic limb movement disorder, and restless leg syndrome. Evaluation of intraepidermal nerve fiber density along with other examinations such as quantitative sudomotor axon reflex testing and tilt table test are currently being utilized to accurately diagnose small fiber neuropathy [22].

Conjunctival, as well as tongue, biopsy is an informative, technically simple, and relatively safe procedure, which can demonstrate the presence of non-caseating granulomas in support of sarcoidosis. Real-time endobronchial ultrasound-guided transbronchial needle aspiration is utilized to examine the mediastinal and hilar lymphadenopathy in patients suspected of sarcoidosis.

In cases when the initial screening tests failed to provide adequate evidence in support of sarcoidosis, a pan-body fluorodeoxyglucose positron emission tomography (FDG-PET) scan should be considered. Studies have shown that FDG-PET is more sensitive than 67gallium nuclear scan in detecting systemic sarcoidosis. In addition, FDG-PET helps visualize neurologic disease activity otherwise not evident on the MRI and when combined with CT (PET/CT) assists neurologist to assess disease activity and response to therapy [23]. 67Gallium nuclear scan is used in clinical practice since it potentially can reveal elevated uptake at the sites of active inflammation (hot spots), which are appropriate for biopsy.

In patients with exclusive CNS sarcoidosis, a tissue biopsy of the region of interest is the most definitive diagnostic test. Biopsy also helps in ruling out alternative diagnoses in patients who do not respond well to immunosuppressive therapy or with worsening disease.

 
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