Residency · Residency · Neurology

CNS Vasculitis and Sarcoidosis

Introduction

Primary angiitis of the central nervous system (PACNS) and neurosarcoidosis are uncommon inflammatory conditions that mimic a broad range of neurological diseases. Both require a high index of suspicion, tissue confirmation when possible, and prolonged immunosuppressive therapy. Misdiagnosis or delayed treatment can lead to irreversible neurological injury.

Primary Angiitis of the Central Nervous System (PACNS)

Overview

PACNS is an inflammatory vasculopathy restricted to the CNS (brain and spinal cord), with no systemic vasculitis involvement by definition. It affects small and medium-sized leptomeningeal and parenchymal vessels. The mean age of onset is 50 years with a slight male predominance. Histopathological patterns include granulomatous, lymphocytic, and necrotizing forms.

Clinical Presentation

Headache occurs in 60-80% of patients and is typically chronic and progressive, often the earliest symptom. Cognitive decline manifests as subacute encephalopathy with confusion and memory loss. Focal neurological deficits include hemiparesis, aphasia, and visual field cuts. Stroke or TIA may be recurrent and involve multiple vascular territories. Seizures occur in approximately 25% of patients. Symptoms evolve over weeks to months, which distinguishes PACNS from atherosclerotic stroke.

Diagnosis

MRI brain shows multifocal T2/FLAIR white matter lesions, infarcts in multiple vascular territories, and leptomeningeal enhancement; a normal MRI essentially excludes PACNS. CSF is abnormal in approximately 90% of cases, showing lymphocytic pleocytosis and elevated protein, and helps exclude infection and malignancy. Conventional angiography demonstrates alternating stenosis and dilation ("beading") of intracranial vessels with a sensitivity of approximately 60% but limited specificity. Brain and leptomeningeal biopsy is the gold standard with a sensitivity of 50-75% depending on sampling, showing non-caseating granulomas, lymphocytic infiltration, or fibrinoid necrosis of vessel walls. Reversible cerebral vasoconstriction syndrome (RCVS) must be excluded because it mimics PACNS angiographically.

PACNS vs. RCVS

RCVS presents with thunderclap headache, normal CSF, and angiographic abnormalities that resolve within 12 weeks. PACNS presents with progressive headache, abnormal CSF, and persistent angiographic findings. Calcium channel blockers help RCVS while immunosuppression helps PACNS.

Treatment

Induction therapy consists of high-dose IV methylprednisolone followed by oral prednisone plus cyclophosphamide for 3-6 months. Maintenance therapy transitions to azathioprine or mycophenolate mofetil for at least 12-18 months. Monitoring involves serial MRI, CSF analysis, and clinical assessments. The relapse rate is significant, and long-term follow-up is essential.

Secondary CNS Vasculitis

CNS involvement can occur in systemic vasculitides including polyarteritis nodosa, granulomatosis with polyangiitis, Behcet disease, and Takayasu arteritis. Infection-associated vasculitis includes varicella-zoster vasculopathy, HIV, syphilis, and fungal angiitis. Drug-induced causes include cocaine and amphetamines. Systemic disease must always be evaluated before diagnosing PACNS.

Neurosarcoidosis

Overview

Neurological involvement occurs in 5-15% of systemic sarcoidosis patients and may be the presenting manifestation in up to 50% of neurosarcoidosis cases. The pathology involves non-caseating granulomatous inflammation with predilection for leptomeninges, cranial nerves, hypothalamus, and spinal cord. Any part of the nervous system can be affected.

Clinical Manifestations

Cranial neuropathies occur in 50-70% of cases, with facial nerve palsy being most common (which may be bilateral) and optic neuropathy second most common. Chronic lymphocytic meningitis produces headache and cranial neuropathies. Hypothalamic-pituitary dysfunction causes diabetes insipidus, hyperprolactinemia, and panhypopituitarism. Parenchymal disease manifests as mass lesions, encephalopathy, and seizures. Spinal cord involvement produces longitudinally extensive myelitis with dorsal subpial enhancement. Peripheral neuropathy includes small fiber neuropathy, mononeuritis multiplex, and polyradiculopathy. Chronic granulomatous myopathy is often subclinical.

Diagnosis

Serum ACE level has a sensitivity of only approximately 60% and is not specific. Chest CT shows bilateral hilar lymphadenopathy in approximately 90% of systemic sarcoidosis cases. Brain MRI demonstrates leptomeningeal enhancement, hypothalamic/pituitary enhancement, cranial nerve enhancement, and parenchymal lesions. CSF shows lymphocytic pleocytosis, elevated protein, low glucose in some cases, and elevated CSF ACE (with low sensitivity). Whole-body PET-CT identifies accessible biopsy sites such as lymph nodes and lungs. Tissue biopsy showing non-caseating granulomas is required for definitive diagnosis; the most accessible site (lymph node, lung, skin) should be biopsied, with brain biopsy reserved for cases without available systemic tissue. The Zajicek criteria classify the diagnosis as definite (CNS tissue confirmation), probable (CNS inflammation plus systemic tissue confirmation), or possible (clinical/radiographic pattern consistent with neurosarcoidosis).

Treatment

First-line therapy is corticosteroids: IV methylprednisolone for acute severe presentations followed by prolonged oral prednisone taper over months. Steroid-sparing agents include methotrexate (the most commonly used), mycophenolate mofetil, and azathioprine. For refractory disease, infliximab (anti-TNF-alpha) has strong evidence in neurosarcoidosis refractory to conventional immunosuppression. Treatment duration is often years because relapses are common with steroid tapering. Monitoring involves serial MRI and clinical assessments every 3-6 months.

Clinical Pearls

PACNS presents with chronic progressive headache and multifocal neurological deficits; it must always be distinguished from RCVS using CSF analysis and clinical tempo. Brain biopsy remains the gold standard for PACNS but has imperfect sensitivity; empiric treatment may be necessary when clinical suspicion is high. Bilateral facial nerve palsy in a young adult should prompt evaluation for sarcoidosis, Lyme disease, and HIV. Infliximab is the preferred biologic for neurosarcoidosis refractory to corticosteroids and conventional immunosuppressants.

References

• Birnbaum J, Hellmann DB. Primary angiitis of the central nervous system. Arch Neurol. 2009;66(6):704-709.
• Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med. 2007;146(1):34-44.
• Fritz D, van de Beek D, Brouwer MC. Clinical features, treatment and outcome in neurosarcoidosis: systematic review and meta-analysis. BMC Neurol. 2016;16(1):220.
• Stern BJ, Royal W 3rd, Gelfand JM, et al. Definition and consensus diagnostic criteria for neurosarcoidosis. JAMA Neurol. 2018;75(12):1546-1553.

Read this lecture as Markdown