Discussion
Sarcoidosis is a multi-systemic disease, characterized by cellular immunity activity with formation of noncaseating granuloma in various organ systems. Diagnosis of sarcoidosis is often a complex, time-consuming trajectory due to the variety of clinical presentations and the fact that laboratory blood and CSF examination is frequently unspecific. As seen in our patient; mononuclear inflammatory cells, elevated protein and occasionally low glucose. Three criteria are required to diagnose sarcoidosis: clinical and matching radiologic manifestations, a histological prove of a noncaseating granuloma and the exclusion of alternative diseases. The Neurosarcoidosis Consortium Consensus Group has developed a diagnostic criterion for neurosarcoidosis3,9. Cranial and peripheral neuropathies are the major presenting symptoms, together with myopathy, seizures, gait disorders and cognitive decline. In 1-7 % the vestibulocochlear nerve is affected 12,13. In the present case, involvement of VIIIth cranial nerve could be suspected due to her unsteadiness with walking.
Neurosarcoidosis in the basal leptomeninges appears as thickening and enhancement (either focal, multifocal or diffuse) on gadolinium-enhanced T1-weighted MRI. It is usually indistinguishable from the pattern seen in tuberculous meningitis or CNS lymphoma 8, which both may have a similar clinical presentation. Therefore, a histological diagnosis of the radiological aberrant tissue is necessary. In tuberculous meningitis, the basal leptomeningeal involvement is known to be due to extension and/ or rupture of a Rich focus (subpial or subependymal focus) to the subarachnoid spaces and ventricular system, which causes enhancement of the exudate14. A similar mechanism in neurosarcoidosis has not been described.
Parenchymal involvement often follows a perivascular spread, with T2/FLAIR hyperintense white matter changes and / or perivascular enhancement 15. The progressive T2 hyperintensities in the deep white matter, observed in our patient, should be interpreted as parenchymal involvement.
The question remains whether the ischemic strokes and progressive vascular white matter changes in our patient, as a consequence of small-vessel disease, can be attributed to neurosarcoidosis. Although rarely, it has been reported that neurosarcoidosis can cause arterial and venous ischemic and hemorrhagic strokes or TIA’s due to granulomatous inflammation of intracranial blood vessels15. This has mainly been described in medium and small vessels, literature of large vessel involvement is scarce and is thought to be due to compression by granuloma’s rather than granulomatous inflammation or vasculitis 1516.
There is still some uncertainty about the underlying pathophysiological mechanism of stroke-like symptoms in patients with sarcoidosis. A retrospective study evaluated patients with sarcoidosis-related strokes and concluded that a stroke was the first presenting symptom in 40% of the patients 16. In about 92% of neurosarcoidosis patients presenting with stroke, sarcoidosis appeared to be present in other non-nervous systems after additional examination. The authors suggest that the granulomatous invasion of the blood vessel walls is the mechanism behind sarcoidosis related cerebrovascular events rather than sarcoidosis related vasculitis. It is thought that vasculitis due to sarcoidosis is more commonly resulting in a slowly progressive encephalopathy than an ischemic stroke 17. A mortality rate of 23% is reported in sarcoidosis patients presenting with stroke16.
Due to the three-year time interval between stroke and diagnosis of neurosarcoidosis, it remains debatable whether this could have been a first warning sign of neurosarcoidosis in our patient.
Hydrocephalus is described to emerge in the course of neurosarcoidosis in 5 to 12% of affected individuals 4. Usually this is a communicating hydrocephalus as a consequence of a decrease in CSF resorption due to leptomeningeal involvement. Though, CSF outflow obstruction caused by involvement of the basal leptomeninges in the inflammatory process and consequent adhesions, loculations in the ventricular system or infiltration of the choroid plexus can also lead to hydrocephalus 18,8.
Scarce literature is available on the treatment of neurosarcoidosis and is mainly based on expert opinion and small retrospective studies. Typically, initial treatment consists of corticosteroids, although the exact mechanism is still unknown. It is hypothesized that the benefit is due to the anti-inflammatory and immune-modulating effects11,19. The benefit of this treatment varies widely from substantial improvement to no improvement at all. As a second step, a steroid-sparing or second-line agent, like Methotrexate (MTX) or mycophenolate can be considered. When the need for immunosuppressive treatment is chronic, upfront start of combination therapy of both corticosteroids and a steroid-sparing or second-line agent can be preferred. Further treatment options include TNF-alpha inhibitors such as infliximab, although treatment is expensive and poses a higher risk for infections and other toxicities 9,19.