Fig. 3.1
Age- and sex-adjusted survival of patients with primary central nervous system vasculitis (PCNSV) versus estimated survival of the US white population (p < 0.001)
Patients with several bilaterally affected large vessels, who rapidly progress with the disease and who suffer numerous recurrent cerebral infarction are more prone to a fatal outcome. By contrast, patients with small vessel vasculitides, prominent leptomeningeal enhancement, negative cerebral angiogram, and positive brain biopsy typically respond rapidly to treatment and have a positive neurological prognosis (Fig. 3.1).
A lower mortality rate has also been observed in patients with MRI gadolinium enhancement of cerebral lesions or the meninges [11]. Some reports have suggested that patients with primary CNS vasculitis diagnosed on the basis of abnormal angiography alone have a more benign course than do those diagnosed by biopsy (particularly in pediatric patients) [12, 13]. However, in other series, the clinical characteristics and outcomes in patients diagnosed by biopsy and angiography were similar [8, 14, 15]. The inclusion of patients who are clinically suggestive of reversible cerebral vasoconstriction syndrome, which usually has a benign course, might account for these differences.
In a case series of 101 patients, mortality was higher than expected [8]. Four indicators at presentation were associated with an increased mortality rate: (1) focal neurological deficit versus headache or constitutional symptoms (HR, 3.60), (2) cognitive impairment versus headache or constitutional symptoms (HR, 4.00), (3) cerebral infarction versus no infarction (HR, 4.39), and (4) large vessel involvement versus small vessel involvement (HR, 7.93) [8].
In addition, disability defined by modified-Rankin Score (m-RS) was directly linked to these factors. Indeed, high disability scores (Rankin scores, 4–6) at last follow-up were associated with presenting manifestations of focal neurological deficit or stroke (OR, 4.09), cognitive impairment (OR, 7.36), cerebral infarction at diagnosis (assessed by MRI; OR, 4.46), and large-vessel involvement (OR, 3.23) [8].
No differences in survival were observed in patients stratified according to treatment (prednisone alone vs prednisone and cyclophosphamide), diagnostic technique (angiography vs biopsy), or other biological or laboratory markers.
The overall mortality rate of the cohort with PCNSV increased, but most survivors improved with relatively low disability scores. Patients with Rankin score of 0–2 at diagnosis continued to have low scores (0–3) at last follow-up evaluation, and most of the patients with severe disability at diagnosis (Rankin score, 4–5) had a disability at follow-up [8].
Fifty-two adult PACNS patients (51 treated with steroids, 44 patients received cyclophosphamide) with a median follow-up of 35 months had a mortality rate of 6 % [15]. Response to first-line steroid therapy was significant in 65 % of cases, 8 % did not respond, and relapses occurred in 27 % [15].
Neurologic damage persisted for 40 survivors (82 %). At last follow-up visit, the modified-Rankin scale score had declined to a median score of one (range 0–5), and 79 % of survivors had scores of two [15]. Finally, in the same cohort, the presence of seizures and the presence of gadolinium-enhanced lesions were predictive of clinical relapses [15].
3.2 Vasculitis Complicating Systemic Diseases
3.2.1 Behçet Disease
Key Facts
Terminology and definitions – Behçet: is a multisystem relapsing inflammatory disorder.
Clinical features – Neurological lesions in Behcet disease may be: (1) parenchymal (subacute brainstem syndromes; cranial nerve, cerebellar, corticospinal involvement) and (2) non-parenchymal mostly characterized by sinus venous thrombosis.
Diagnostic markers – Focal CNS deficits with mouth and genital sores, uveitis, arthropathies, skin rashes, and dermographism characterize parenchymal Neuro-Behçet; headache and a pseudotumor cerebri–like picture indicate non-parenchymal neuro-BD.
Laboratory – CSF may show aseptic meningitis.
Imaging – Diffuse lesions in the brainstem or basal ganglia extending to the diencephalon are the most common parenchymal findings.
Top differential diagnoses – Multiple sclerosis, SLE, sarcoidosis.
Prognosis – Mortality rate may be high. In parenchymal forms disability is frequent, whereas non-parenchymal NB has a better prognosis.
Principles of treatment – Steroids and immunosuppressive therapy might be efficacious in parenchymal form. Anticoagulation plays a pivotal role in cases of venous thrombosis.
3.2.1.1 Terminology and Definitions
Behçet disease (BD) is a multisystem relapsing inflammatory disorder of unknown cause characterized by recurrent orogenital ulcers, ocular inflammatory disease, thrombophlebitis, and various cutaneous manifestations.
3.2.1.2 Demographics and Clinical Features
Neuro-Behçet disease (NBD) occurs in 10–49 % of patients with BD; male predominance is 4:1 [16, 17].
Two different clinical syndromes are described. The most common form, due to an immune-mediated meningoencephalitis, involves the brainstem and is called parenchymal Neuro-Behçet. The second one, named non-parenchymal NBD, is the consequence of thrombosis and inflammation within the dural venous sinuses and, rarely, within the cerebral arteries [17, 18]. Parenchymal CNS involvement is often a subacute brainstem syndrome with cranial nerve findings, dysarthria, and cerebellar or corticospinal tract signs. Uncommon presentations include stroke-like episodes, seizures, and psychiatric features.
Non-parenchymal NBD is mostly characterized by sinus venous thrombosis that may result in intracranial hypertension with headache, vomiting, and bilateral papilledema. Arterial involvement is rarer and leads to ischemic stroke or subarachnoid hemorrhage.
Neurological symptoms represent the first manifestation of Bechet only in 3 % of cases [18].
3.2.1.3 Diagnostic Markers
The diagnosis of Behcet’s disease is entirely based on clinical grounds: no pathognomonic laboratory or histological findings exist. The association of T2 hyperintense CNS lesions in the presence of oral and genital ulcers is the best diagnostic clue.
Blood
Association to HLA-B51 may be present in severe cases.
CSF
Abnormal in 70–80 % of parenchymal NB, with raised proteins in most cases.
MRI
May show focal or diffuse lesions mostly in brainstem or basal ganglia to the diencephalon [19]. Lesions may be localized within the subcortical white matter and hypothalamic regions. Venous sinus thrombosis can be demonstrated by magnetic resonance and brain CT venography.
3.2.1.4 Prognosis
Therapy
In acute episodes of parenchymal NBD, corticosteroids (oral prednisolone: 1 mg/kg, or with high-dose intravenous methylprednisolone (1 g/day) for 3–7 days) have a short-lived effect and do not prevent further attacks or progression. Colchicine, azathioprine, cyclosporine-A, cyclophosphamide, methotrexate, chlorambucil, and immunomodulatory agents such as IFN-a, pentoxyphilline, and thalidomide have been anecdotally reported useful in treating some of the systemic manifestations of BS, but none of them are effective in NBD [16, 17].
Disability
Most patients with an acute parenchymal inflammatory episode improve after steroid treatment. Retrospective series reported a mean of 20–30 % of patients with residual neurological impairments and 10 % mortality rate at 10 years [16, 20]. NBD is a significant cause of morbidity. Ten years after the onset of neurological deficits, 78.2 % of patients were found to develop at least mild (EDSS ≥3), and 45.1 % moderate to severe neurological disability (EDSS ≥6) [16]. On the contrary, patients affected by non-parenchymal NBD had minimal disability with EDSS scores of one or two.
About a third of patients had single episodes, a third had repeated relapses and remission, and a third underwent a progressive disease course with accrual of neurological impairments [16].
Adverse prognostic factors included: (a) progressive course, (b) frequent relapses, and (c) residual neurological impairments during remissions [20]. Patients with brainstem and spinal cord lesions recovered less well; elevated proteins and pleocytosis in the CSF were also associated with poorer prognosis [16].
Patients with silent neurological involvement tend to regress toward clinically evident deficits.
Appropriate treatment may improve and reduce the risk of recurrence of venous sinus thrombosis and intracranial hypertension.
3.2.2 Sarcoidosis
Key Facts
Terminology and definitions – Sarcoidosis is a granulomatous disorder that affects multiple organs. Neurosarcoidosis affected 5 % of patients with sarcoidosis.
Clinical features – Cranial neuropathies (from second to seventh cranial nerves), aseptic meningitis, seizures, hydrocephalus, and PNS deficits.
Diagnostic markers – Based mostly on clinical findings.
CSF – Might show hypoglycorrhachia, mononuclear pleocytosis and high titer of angiotensin-converting enzyme. Biopsy might be helpful.
MRI – Leptomeningeal enhancement (particularly at the skull base) is typically present. Hypothalamus, infundibulum, and pituitary gland might also be involved.
Top differential diagnoses – Tuberculosis, neoplasia, infectious meningitis, MS, SLE.
Prognosis – PNS involvement carries good prognosis; CNS involvement often causes disability.
Principles of treatment – Steroids and immunosuppressive drugs.
3.2.2.1 Terminology and Definitions
Sarcoidosis is a granulomatous disorder that affects multiple organs. Five percent of patients with sarcoidosis have nervous system localizations (neurosarcoidosis).
3.2.2.2 Demographics
Neurosarcoidosis (NS) more commonly occurs with other sarcoidosis forms; in 1 % of cases it involves only the nervous system.
3.2.2.3 Clinical Features
Cranial neuropathies are the most common manifestations of neurosarcoidosis (50–75 %), with facial nerve palsy being the most frequent symptom (25–50 %). Sarcoidosis-related optic neuritis is an emergency because permanent vision loss may occur [21]. Hydrocephalus has been described in 5–7 % of cases. Headache due to meningitis, encephalopathy, mass lesions, or hydrocephalus are further common manifestations. Fifteen percent of patients will develop seizures. Several neuropsychiatric conditions, including depression, and psychosis may be associated. Neuroendocrine dysfunctions may be caused by sarcoid granulomas of hypothalamic-hypophysial complex [21, 22].
3.2.2.4 Diagnostic Markers
Biopsy
Patients without known systemic sarcoidosis who develop a brain or spinal cord mass are usually biopsied for definitive diagnosis.
3.2.2.5 Therapy
No well-designed study delineates the optimal treatment of neurosarcoidosis. A goal of treatment is to diminish the irreversible fibrosis that can develop, as well as the tissue ischemia that might result from perivascular inflammation [26]. The inflammatory process may become quiescent with time.
Corticosteroids are the first-line treatment of sarcoidosis. In general, neurosarcoidosis is less responsive to corticosteroids than sarcoidosis of other body parts.
More than 70 % of patients treated with corticosteroids alone developed neurological deterioration. Immunomodulating and cytotoxic agents such as azathioprine, cyclophosphamide, or methotrexate have been shown to improve the neurological outcome in approximately one-fifth of cases of neurosarcoidosis refractory to corticosteroids [26, 27].
A combination of corticosteroids with either methotrexate, azathioprine, or cyclophosphamide has resulted in a favorable outcome in neurosarcoidosis patients with severe CNS involvement.
3.2.2.6 Prognosis
Long-term clinical outcome of neurosarcoidosis has rarely been evaluated.
Approximately two-thirds of patients have a monophasic neurological illness; the remainder display chronically progressive or a remitting–relapsing course. Whether treatment changes the natural history of the disease is not proven, though in the short-term symptoms can often be relieved by therapy [21, 24, 26].
Generally, PNS involvement has a more favorable clinical outcome than CNS localized disease. No correlation between extra-neurological manifestations and clinical outcome exist, suggesting that systemic involvement is not a predictive factor for the evolution of neurosarcoidosis. Optic nerve atrophy has bad prognosis. On the contrary, facial nerve palsies tend to have a good prognosis [21, 27, 28]. Hydrocephalus is a rare manifestation of sarcoidosis with poor long-term prognosis [27].
Spinal cord neurosarcoidosis occurs in <1 % of patient, but often causes severe neurological sequelae [28]. In general, people with cranial neuropathy (except optic neuropathy), acute meningitis, or peripheral neuropathy have a lower risk for progression and long-term disability than patients with intracranial disease.
Indeed, CNS involvement causes severe conditions and higher morbidity and mortality [27, 28]. Seizures and intense gadolinium enhancement are also linked to poor prognosis.
One-third of patients display refractory forms of NS with higher morbidity and mortality. Laboratory findings (including CSF and blood) do not predict refractory NS; in addition, the common markers of disease activity (blood and CSF ACE, gallium scintigraphy) do not correlate with clinical outcome [28].
3.2.3 Primary Sjögren Syndrome (PSS)
Key Facts
Terminology and definitions – (Synonyms: Sicca syndrome, Gougerot-Sjögren syndrome). Autoimmune disease affecting exocrine glands and extraglandular organs including both PNS and CNS.
Clinical features – Keratoconjunctivitis sicca and xerostomia are the typical findings [29]. Peripheral neuropathies are observed in 25 % of cases. Aseptic meningoencephalitis and psychiatric or cognitive symptoms are emblematic of CNS involvement.
Diagnostic markers
Blood – Antibody against extractable RNA proteins Ro are found in Sjögren syndrome A (SS-A); antibody against intranuclear RNA-associated antigen La are found in Sjògren syndrome-B (SS-B).
MRI – Is the first choice examination for spinal cord lesion or deep and subcortical white matter alterations.
Top differential diagnoses – Multiple sclerosis, neuromyelitis optica, SLE.
Prognosis – Better outcome in patients with PNS than CNS involvement.
Principles of treatment – Steroids and immunosuppressive drugs.
3.2.3.1 Clinical Features
More than 90 % of people affected by Sjögren’s (0.5–1 % of the population in USA) syndrome are women. The disease is most often seen in the sixth decade of life. The prevalence of its neurological manifestations (more often of CNS than PNS) varies between 10 and 60 % of all PSS.
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