NEUROSARCOIDOSIS

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NEUROSARCOIDOSIS:

NEUROSARCOIDOSIS R A V I K I R A N P A D A L A

A few words about Sarcoidosis:

A few words about Sarcoidosis Multisystem granulomatous disorder Characterized by the presence of noncaseating granulomas in involved organs Typically affects young adults Initially presents with one of the following: Bilateral hilar adenopathy Pulmonary reticular opacities Skin, joint, and/or eye lesions ~ 50% of cases are incidental diagnoses

NEUROSARCOID:

Neurologic complications occur in approximately 5 percent of patients with sarcoidosis ~ 50 percent of patients with neurosarcoidosis present with neurologic difficulties at the time sarcoidosis is first diagnosed. One-third of those with neurosarcoidosis have or develop more than one neurologic manifestation NEUROSARCOID

PATHOPHYSIOLOGY:

NON-CASEATING GRANULOMAS Made up of EPITHELOID CELLS,GIANT CELLS,CENTRAL CD4 CELLS,PERIPHERAL CD8+ cells, B lymphocytes Increased production of IL-2,INF-gamma, TNF-alpha ultimately FIBROSIS with production of IL-4 , 10 , 13.. PATHOPHYSIOLOGY

Cranial neuropathies:

Olfactory nerve - Altered olfaction-olfactory nerve compromise or granulomatous sinus inflammation Optic nerve - optic disc edema, retrobulbar optic neuropathy & optic atrophy Trigeminal nerve- numbness, parasthesias , hyperpathia & dysesthesia Facial nerve : PERIPHERAL FACIAL NERVE PALSY Unilateral or Bilateral Simultaneous/sequential/recurrent Cranial nerve VIII - Hearing or vestibular dysfunction Cranial neuropathies CLINICAL FEATURES

CNS PARENCHYMAL DISEASE:

Assosciated leptomeningeal inflammation should raise suspicion of sarcoidosis Common site DIENCEPHALON Single or multiple mass lesions Strokes -intracranial large artery inflammation& perivascualar small artery inflammation. Seizures Granulomatous inflammation in a perivascular distribution can produce partial or generalized seizures, or restricted or generalized encephalopathy/ vasculopathy . Simple and complex partial seizures.. Non specific deep & superficial white matter lesions CNS PARENCHYMAL DISEASE

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Neuroendocrine dysfunction One of most common CNS parenchymal manifestations usually due to hypothalamic inflammation, resulting in polyuria or disturbances in sleep, appetite, temperature, or libido. Direct hypothalamic involvement can lead to central diabetes insipidus or primary polydipsia, hypercalcemia (due to production of calcitriol by activated macrophages) can cause nephrogenic diabetes insipidus Spinal cord disease -extradural or inradural granulomatous mass lesion or a diffuse or fairly discrete intramedullary lesion ….., SPINAL CORD ATROPHY Myelopathy or radiculopathy Due to Granulomatous inflammation affecting the spinal cord, can be extramedullary or intramedullary, and the cauda equina can be involved

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Cavernous sinus syndrome : characterised by nerve involvementof oculomotor , trochlear, abducensand the ophthalmic and maxillary divisions of the trigeminal nerve. MRI scan usually show variable enhancement associated with involvement of orbital muscles Differential diagnoses includes meningioma , lymphoma, glioma .

LEPTOMENINGEAL INVOLVEMENT:

Leptomeningeal infiltration is common: 8 to 64% ofpatients . Leptomeningeal infiltration typically involves the suprasellar , frontal basal meninges and basilar cisterns. Meningeal involvement is in the form of nodules or plaques , showing focal or diffuse thickening on contrastenhanced CT and MRI. These findings are rather nonspecific and are also seen in meningitis , meningiomas , metastases, lymphomas andplasmocytomas . LEPTOMENINGEAL INVOLVEMENT

More clinical features:

Hydrocephalus may develop acutely or subacutely ; if present is usually incidentally detected by imaging studies. Meningeal involvement can take the form of either an acute aseptic meningitis or a chronic meningitis. Meningeal mass lesions also can develop . Peripheral neuropathy electromyography usually reveals an axonal neuropathy. acute generalized demyelinating motor neuropathy similar to the Guillain-Barré syndrome also has been described Carpal tunnel syndrome appears to be more common among patients with sarcoidosis than the general population Muscular involvement includes asymptomatic microscopic nodules, isolated palpable nodules, an acute or chronic proximal myopathy, and muscle atrophy Headache (60 %) Signs of increased intracranial pressure (30%) More clinical features

ISOLATED CNS SARCOIDOSIS:

Yet to be codified with specified criteria Patients exhibit multifocal intraparenchymal lesions,encephalopathy & hydrocephalus faring worse Kveim test results – inconsistent,sometimes POSITIVE. CNS BIOPSY- when lesions mimic brain tumours ., Outcome favourable in single extra axial lesions and minimal preop deficits ISOLATED CNS SARCOIDOSIS

DEFINTIONS FOR DIAGNOSIS:

DEFINTIONS FOR DIAGNOSIS POSSIBLE : CLINICAL SYNDROME & DIAGNOSTIC EVALUATION s/o NS ., INFECTION &MALIGNANCY NOT TO EXCLUDE NO PATHOLOGIC CONFIRMATION OF SYSTEMIC SARCOIDOSIS PROBABLE : CLINICAL SYNDROME & DIAGNOSTIC EVALUATION s/o NS.., ALTERNATE DIAGNOSIS EXCLUDED.., PATHOLOGIC CONFIRMATION OF SYSTEMIC SARCOIDOSIS .., DEFINITE : CLINICAL PRESENTATION s/o N.S.., Exclude other diagnosis Supportive nervous system pathology or criteria for PROBABLE NS met Beneficial response to immunotherapy

DIAGNOSIS:

If neurosarcoidosis is suspected, the patient should be evaluated for evidence of extraneural disease because obtaining nerve tissue for diagnostic evaluation is often difficult. Thoroughly evaluate skin, lymph nodes, lungs Eyes Endoscopic nasal and sinus examination Computed tomographic scan of the chest to look for hilar adenopathy or parenchymal changes In rare cases, a magnetic resonance, gallium, or fluorodeoxyglucose positron emission tomographic scan, may highlight otherwise occult areas of inflammation that might be amenable to biopsy DIAGNOSIS

DIAGNOSIS:

Serum angiotensin converting enzyme may be helpful if elevated BUT not specific or sensitive ACE concentration may not necessarily be elevated if the patient has isolated neurosarcoidosis !! Neurologic evaluation should proceed if no extraneural tissue is available for biopsy . Unfortunately, no neurodiagnostic tests are pathognomonic for neurosarcoidosis Presumptive diagnosis of neurosarcoidosis is often made on the basis of MRI and lumbar puncture results in the appropriate clinical setting DIAGNOSIS

Neurodiagnostic testing:

Cerebrospinal fluid (CSF) abnormalities occur frequently in patients with CNS sarcoidosis: elevated opening pressure in approximately 10 percent of patients total protein is increased in two-thirds of patients, typically up to 250 mg/dL pleocytosis is present in approximately 50 percent of patients, usually mononuclear Glucose can be normal or low, as can be seen in CNS infections or carcinomatous meningitis oligoclonal bands may be present CSF ACE concentration is occasionally elevated, but reliable normal values are lacking and CSF ACE may also be increased with infection or carcinomatous meningitis EMG , evoked potentials, and angiography, are occasionally indicated to exclude other conditions and can help localize neuromuscular lesions. If the diagnosis remains in doubt, meningeal, brain, or spinal cord biopsy is occasionally indicated. Biopsy to establish the diagnosis, rather than empiric therapy, should be considered if there is no defined systemic disease Neurodiagnostic testing

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TEST RESULT COMMENTS PROTEIN NORMAL or HIGH Very high>100mg/dl CELLS NORMAL or MODERATELY HIGH LYMPHOCYTIC, PMN’s GLUCOSE NORMAL or LOW ACE NORMAL or ELEVATED Not easily cross brain IGg & oligoclonal bands NORMAL or INCREASED VIRAL PCR’s NEGATIVE R/O HERPES FAMILY PRIMARILY FUNGAL &TB STAIN&CULTURE NEGATIVE R/o infection CYTOLOGY NEGATIVE R/o carcinomatous meningitis

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Diagnostic flow chart for pat. with act. sarc. and presentation with neurological symptoms

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Diagnostic flow chart for patients not known to have sarcoidosis or with inactive disease with neurological symptoms

Differential diagnosis:

Cranial nerve dysfunction — idiopathic Bell's palsy facial neuropathy associated with Lyme disease. multiple sclerosis-associated optic neuritis. Chronic infections, such as tuberculosis, and carcinomatous or lymphomatous meningitis should be considered in patients with multiple cranial nerve palsies. Parenchymal lesions — Parenchymal granulomatous masses can masquerade as an astrocytoma or other primary or metastatic brain tumors. Encephalopathy — The encephalopathy/vasculopathy of sarcoidosis can be difficult to distinguish from syphilis or CNS vasculitis. Meningeal disease — Sarcoidosis-associated aseptic meningitis is indistinguishable from that caused by viral infections, including HIV, or by tuberculosis or syphilis. A granulomatous meningeal mass may look like a meningioma on imaging studies. Peripheral neuropathy — toxin exposure, metabolic abnormalities, inflammatory disorders. Muscle weakness — Polymyositis and other causes of acquired muscle weakness need to be considered if a myopathic process is identified. Differential diagnosis

DIFFERENTIAL DIAGNOSIS:

Multiple sclerosis Neuromyelitis optica CNS Lymphoma Leptomeningeal metastasis Fungal meningitis Tubercular meningitis Tuberculoma Wegner granulomatosis Sjogren syndrome-related vasculitis Behcet disease Toxoplasmosis Neurobrucellosis Germ cell tumours Primary CNS neoplasia Neurosyphilis Neurobrucellosis Neuroborreliosis Human immunodeficiency virus infection Cytomegalovirus ventriculitis or polyradiculopathy etc., DIFFERENTIAL DIAGNOSIS

TREATMENT:

CLINICAL SYMPTOM CONTROL NEUROLOGICAL CONTROL KEY GOALS OF THERAPEUTICS IN NS TREATMENT

TREATMENT:

Corticosteroids BUT no randomized, double blind, placebo-controlled treatment trials for neurosarcoidosis . dose and duration of therapy should be dictated by disease severity and response to therapy Frequent clinical evaluation and periodic assessment of the extent of MRI enhancement (if enhancement was present on pretreatment scans) are generally helpful to monitor disease as steroids are weaned monitoring of nerve conduction velocities and the electromyogram is occasionally useful BUT titrating therapy to normalize CSF parameters is not recommended because excessive immunosuppression frequently results from this practice. DOSE: PREDNISONE -- 0.5 TO 1 mg/kg/day --- orally Methyl predinosolone -- 1g/d OR 20mg/kg/d for 3-5 days – I.V Reserved for SEVERE MYELOPATHY, MASS EFFECT ASSOSCIATED INTRAPARENCHYMAL CNS LESIONS, HYDROCEPHALUS WITH INCREASED INTRACRANIAL PRESSURE TREATMENT

CORTICOSTEROIDS (cont…):

Prolong therapy required for parenchymal or severe leptomeningeal disease after bolus therapy, a sustained course of oral predinosone..moinitor close to avoid relapse RELAPSE if therapy is TAPERED OFF or DISONTINUED TOO EARLY For SUSTAINED REMISSION 12 or more MONTHS therapy Severe side effects—transition to ALTERNATE DAY THERAPY BY TAPERING ALT-DAY DOSE TO ZERO CORTICOSTEROIDS (cont…)

Five Phases of Corticosteroid Treatment:

a Five Phases of Corticosteroid Treatment

Alternative therapies:

deteriorate in spite of aggressive corticosteroid treatment, who cannot tolerate steroids, or contraindication to corticosteroid treatment BUT there are no studies comparing various alternative treatments to one another in patients with neurosarcoidosis Other immunosuppresants : azathioprine, methotrexate, mycofenolate , cyclophosphamide, cyclosporin , chlorambucil Infliximab( Remicade ) is a chimeric human-murine antihuman antibody that specifically blocks the effect of tumor necrosis factor-alpha (TNF-alpha). 5mg/kg Immunomodulatory agents used in the management of neurosarcoidosis include hydroxychloroquine , pentoxifyline , thalidomide Alternative therapies

More alternatives:

Surgery Resection of a CNS mass lesion is rarely indicated, and patients may deteriorate following attempted resection of a mass. Ventricular drain can be life saving in patients with acute hydrocephalus. Radiation therapy — for refractory disease considered if patients fail corticosteroid therapy and trials of at least two alternative agents More alternatives

PROGNOSIS:

Approximately 10 percent of patients die as a direct result of the inflammatory process or its treatment. CNS parenchymal disease or hydrocephalus and are often profoundly immunocompromised due to treatment. Patients with a peripheral facial nerve palsy tend to improve over two to four weeks. Optic neuropathy can improve over several weeks, but some patients have a progressive course ending in blindness. Aseptic meningitis usually resolves over several weeks, although an asymptomatic chronic pleocytosis can persist. Peripheral neuropathic and myopathic illness tends to be chronic and progressive, although remissions are possible. PROGNOSIS

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