Inflammatory Central Nervous System Disorders

Approach to Inflammatory Brain Disorders

Inflammatory disorders of the central nervous system encompass an array of acquired diseases characterized by relapsing or progressive clinical deficits and by neuroimaging features suggestive of focal inflammatory lesions. Lesions may involve the white matter predominantly (multiple sclerosis, neuromyelitis optica spectrum disorders), cortical tissue (cerebritis), or vascular structures (vasculitides). Antibody-meditated encephalopathies may have variably severe, subtle, or absent imaging signatures. Secondary involvement of the central nervous system (CNS) in “traditional” rheumatic disorders in neuropsychiatric systemic lupus erythematosus (NP-SLE), antiphospholipid antibody syndrome, neuro-Behçet, or neurosarcoidosis can also manifest with acquired neurological deficits associated with imaging features consistent with inflammatory lesions. Finally, genetically defined leukodystrophies, several mitochondrial diseases, and novel autoinflammatory or immune dysregulatory disorders may also have some features of CNS inflammation. In some instances, monogenic diseases (such as DARS2-associated leukoencephalopathy, or acute necrotizing encephalopathy [ANE]) may have some response to immunomodulatory therapy, making it challenging to distinguish from acquired idiopathic inflammatory brain disorders.

It is also imperative to consider infection, and investigations to exclude CNS infection should be considered as a first priority. Infections with mycoplasma, influenza A, parainfluenza, enterovirus, Epstein–Barr virus, varicella zoster virus, cytomegalovirus, and herpes simplex virus are important infectious causes of encephalitis, and both symptoms and magnetic resonance imaging (MRI) features may overlap with those of idiopathic inflammatory brain disorders. The distinction between active CNS infection and postinfectious CNS inflammation can be difficult. Acute presence of organisms in the CNS, as demonstrated by cerebrospinal fluid (CSF) culture, polymerase chain reaction against viral DNA, or tissue biopsy, often identifies children with an infectious process. An interplay between host genetic factors ( RANBP2 or Toll-like receptor-3 mutations) and specific infections (influenza, herpes simplex virus) must be considered in severe neurological dysfunction. Finally, CNS malignancy must also be considered, as some hematological malignancies can initially resemble inflammatory conditions. Transient responses to corticosteroids are common in lymphomatous or leukemic CNS lesions and in glial tumors with peri-tumoral edema.

The care of children with inflammatory brain disorders rests with pediatric neurologists and rheumatologists, or both, and may require consultation with pediatric oncologists given the array of immunomodulatory options more commonly prescribed by each specialty. Partnered care and shared expertise enhances outcome, improves diagnostic efficiency, and ensures careful consideration of treatment options, benefits, and risks. Consultation with genetics and immunology may aid in the identification of children with genetic disorders and primary syndromes of immune dysregulation.

In this chapter, we focus on several of the more common inflammatory brain disorders, provide a diagnostic approach, and discuss currently accepted therapeutic options.

Diagnostic Approach to Inflammatory CNS Disorders

As outlined in Table 31.1 , inflammatory brain disorders can be broadly categorized by the primary presumed “target” of the CNS-directed immune response. Although such a conceptualization may be helpful from a diagnostic and therapeutic perspective, it is important to acknowledge that the inflammatory response, and certainly the extent of tissue injury, is rarely completely confined to these key CNS tissues or isolated immune pathways. It is also important to emphasize that mechanisms of disease are only partially understood, even in disorders with specific immune signatures.

The clinical manifestations of the relapsing inflammatory brain disorders largely relate to the CNS region involved in the acute inflammatory episode. Common clinical manifestations include inflammation of the optic nerves (optic neuritis), which are characterized by reduced visual acuity, enlarged blind spot or central scotoma, pain with ocular movements, and red-green color desaturation. Spinal cord lesions present with one or more of motor impairment, sensory loss (with a localized sensory level), bowel and bladder impairment, and pain with neck flexion (Lhermitte symptom). Brainstem inflammation leads to cranial nerve deficits, such as internuclear ophthalmoplegia, diencephalic involvement resulting in hypersomnolence, hiccups, hyperphagia, and other symptoms, whereas cerebellar involvement impairs gait balance, as well as dysmetria, dysarthria, and impairment of rapid alternating movements. Cerebral lesions can lead to focal motor or sensory deficits, with widespread cerebral lesions often associating with encephalopathy (reduced level of awareness, confusion, delirium). Cortical involvement can lead to seizures. Vascular inflammation manifests as cerebral ischemia and stroke. Involvement of the basal ganglia, such as in N-methyl- d -aspartate (NMDA)-receptor encephalitis (and other autoimmune encephalopathies [AE]), leads to dystonia, catatonia, and often diffuse cerebral impairment manifesting as a marked impairment in awareness, seizures, and/or obtundation.

Whereas most inflammatory brain disorders begin with an acute attack, the course (if untreated) may follow a relapsing-remitting phenotype (typified by multiple sclerosis, neuromyelitis optica-spectrum disorders, and others) or a more progressive course (as seen in small-vessel CNS vasculitis, anti-NMDA receptor encephalitis, or paraneoplastic encephalopathies).

Standardized, consensus-driven treatment protocols and clinical trials are often lacking, but best practice favors prompt diagnosis and rapid initiation of immune-suppressive or immunomodulatory therapy both to improve the acute deficits and as a means of chronic disease maintenance. Supportive care, including treatment of movement disorders, seizures, encephalopathy, and psychiatric manifestations, is also required. Many children require in-hospital care or even intensive care admission at disease onset, and some require prolonged rehabilitative care.

We will focus on the more commonly seen inflammatory brain disorders and prioritize those more likely to fall under the domain of rheumatology. Table 31.1 outlines general categories and key features of the different inflammatory brain disorders, and Table 31.2 summarizes noninflammatory disorders to be considered in the broad differential diagnosis.

General Approach to Inflammatory Brain Disorders

Serum, CSF, and genetic analyses are important when evaluating children with possible immune-mediated inflammatory brain disorders. Identification and validation of serum biomarkers for specific disorders is a promising and burgeoning field. The importance of assay validation, the challenges of novel biomarker discovery, and the research priorities for the future were summarized in an international consensus document. Antibodies directed against the astrocytic water channel aquaporin 4 (AQP4) identify children with neuromyelitis optica spectrum disorder (NMOSD), and antibodies against myelin oligodendrocyte glycoprotein (MOG) are common in children with acute disseminated encephalomyelitis (ADEM) and in children with AQP4-negative NMOSD. CSF inflammatory markers such as white blood cell count and protein are often markedly elevated in infections, small-vessel vasculitis, and some patients with antibody-associated encephalopathy. CSF protein levels are elevated in some acquired and genetic demyelinating conditions, whereas CSF profiles are typically normal in medium–large-sized vessel vasculitis. Elevated opening pressure is seen in over 50% of children with CNS vasculitis. The presence of oligoclonal bands supports the intrathecal synthesis of immunoglobulins (humoral response) and is the hallmark of multiple sclerosis (MS). It is imperative that clinicians understand the diagnostic accuracy and methodology of testing employed by the laboratories to which samples are sent and that samples are obtained at the appropriate time in the diagnostic evaluation and prior to administration of therapies that may alter test sensitivity. Clinicians must be aware that diagnostic tests should only be sent in the appropriate clinical context.

MRI, magnetic resonance angiography (MRA), computed tomography angiography (CTA), formal vessel angiography, optical coherence tomography (OCT), and, potentially, positron emission tomography (PET) all have the potential to visualize inflammatory responses in the optic nerves, brain, and/or spinal cord. High-quality images, aided by direct communication between clinicians and neuroradiologists, are essential. Although no single imaging protocol is applicable across all inflammatory brain disorders, most MR scans include T2-weighted images to detect areas of increased water/inflammation and administration of gadolinium with T1-weighted images to detect disruption of the blood-brain barrier. Serial imaging is required to detect subclinical new disease activity, and concurrent images aid in determination of the extent of inflammation at the time of relapse. Progressive loss of brain volume is common in chronic conditions and often correlates with nonrelapse-related clinical deficits, such as cognitive impairment. Quantification of brain volumes requires research-level imaging and strict comparisons to normative age- and sex-matched metrics.

Specific Inflammatory Brain Conditions

Primary Angiitis of the CNS

Inflammation of the vessels of the CNS may occur as part of a systemic vasculitis; result from infectious or neoplastic disease, metabolic diseases, medication, or radiation therapy; or be restricted to the CNS, so-called primary CNS vasculitis (or primary angiitis of the CNS). Calabrese et al. first systematically reviewed primary CNS vasculitis in adults, proposed diagnostic criteria, and suggested a clinical approach.

Primary CNS angiitis is, by definition, inflammation of vessels of the brain that is not associated with vasculitis of any other organ. The diagnosis of childhood-onset primary angiitis of the CNS (cPACNS) is commonly based on the Calabrese criteria proposed for adult PACNS, which are then further defined by the size of involved vessels. Small-vessel vasculitis cPACNS involves vessels throughout the brain and meninges that are not primary branches of the circle of Willis; large-vessel vasculitis primarily targets major arteries, such as the anterior, middle, and posterior cerebral arteries and the vertebral and cerebellar arteries.

An estimated 40% to 60% of arterial ischemic strokes (AIS) in children are thought to be related to CNS vasculitis, and the overall incidence of childhood AIS is estimated at 3.3 to 7.9 per 100,000 children per year, with a male predominance. Boys are more commonly affected with medium–large vessel cPACNS consistent with the male predominance of childhood AIS in general. In contrast, small-vessel vasculitis is more commonly seen in girls. In the cohort reported by Benseler et al., the mean age at diagnosis was 7.2 years (range, 0.7 to 17.6 years). Small-vessel disease can also manifest with gradual onset of diffuse signs and symptoms, such as headaches, behavioral changes, academic or cognitive decline, or seizures.

In primary large-vessel angiitis, the anterior vasculature is most commonly affected, although up to 30% of children will have inflammation of both anterior and posterior vessels. A small subgroup of children have inflammation affecting only the posterior basilar system, which associates with progressive and severe disease. Children with medium–large-vessel cPACNS usually present with focal deficits and headache. They may have fine motor deficits, cranial neuropathies, movement disorders, and other symptoms corresponding to the stenosis of specific cerebral vessels and their vascular distributions ( Tables 31.3 and 31.4 ).

TABLE 31.3

Clinical Characteristics at Diagnosis of Large-Vessel and Small-Vessel cPACNS

Modified from Twilt et al. Pres-Final-2362: the spectrum of childhood inflammatory brain diseases: an increasingly recognized field. Pediatr Rheumatol . 2013;11(Suppl 2):352.

	Large-Vessel cPACNS Angiography Positive	Small-Vessel cPACNS Angiography Negative
	N = 144	N = 58
Reduced level of consciousness	5%	38%
Focal Deficit
Hemiparesis	72%	14%
Focal gross motor deficit	88%	22%
Focal fine motor deficit	90%	54%
Gait abnormality	86%	62%
Hemisensory deficit	64%	18%
Language deficit	52%	78%
Cranial nerve deficit	64%	14%
Optic neuritis	0%	10%
Ataxia, chorea, dystonia	14%	17%
Diffuse Deficit
Cognitive dysfunction	42%	69%
Memory deficit	32%	64%
Behavior abnormality	38%	66%
Concentration deficit	34%	64%
Seizures
Focal	10%	69%
Generalized	4%	33%
Status epilepticus	0%	24%

TABLE 31.4

Diagnostic Investigations in Childhood Central Nervous System Vasculitis

History	Neurological review of systems (focal, headaches, seizures, other)
	Past medical history
	Family history
	Infectious exposures/risk factors for stroke
	History of skin, ophthalmological, joint involvement, recurrent fevers
Physical examination	Vital signs, peripheral pulses
	General and neurological examinations
	Rheumatologic assessment
	Neurological and neuropsychological assessment
Laboratory investigation	Markers of inflammation: CBC, CRP, ESR, IgG, C3, vWF
	Prothrombotic markers: Protein S and C, antithrombin III, fibrinogen, plasminogen, homocysteine; factor V Leiden, prothrombin gene mutations, lupus anticoagulant
	Autoantibodies: ANA, ENA, dsDNA, ANCA, APLA, aCL, LAC (depending on the differential diagnosis: NMDAR, VGKC-associated Ab, GAD, GABA)
	Infectious serology: Borrelia burgdorferi, VDRL, HIV, VZV ∗
Lumbar CSF analysis	Opening pressure, cell count, protein, glucose, IgG, oligoclonal bands (present in CSF but not in serum)
	Cryptococcal antigen, VDRL, antiviral IgG
	Paired serum and CSF B. burgdorferi and anti-VZV IgG
	Bacterial, fungal, TB cultures
	CSF autoantibodies
Neuroimaging †	CT/CTA
	MRI/MRA with gadolinium and vessel wall imaging
	Cerebral angiography
	Brain SPECT
	PET/CT
	Doppler ultrasound
Tissue biopsies	Brain and overlying meninges
	Skin, nerve, muscle as indicated

aCL, Anticardiolipin antibodies; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; APLA, antiphospholipid antibodies; C3, complement component 3; CBC, complete blood count; CRP, C-reactive protein; CSF, cerebrospinal fluid; CT, computed tomography; CTA, computed tomography angiography; dsDNA, double-stranded DNA antibody; ENA, extractable nuclear antibody; ESR, erythrocyte sedimentation rate; GABA, γ-aminobutyric acid; GAD, glutamate decarboxylase; HIV, human immunodeficiency virus; IgG, immunoglobulin G; LAC, lupus anticoagulant; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; NMDAR, N -methyl- d -aspartate receptor; PET, positron emission tomography; SPECT, single-photon emission computed tomography; TB, tuberculosis; VDRL, Venereal Disease Research Laboratory; VGKC, voltage-gated calcium channel; vWF, von Willebrand factor; VZV, varicella-zoster virus.

∗ Infectious workup will depend on season, regional epidemiology, and/or travel.

† Neuroimaging evaluations will depend on case presentation and judgment of consultants.

The syndrome of a unilateral and focal medium–large cerebral arteriopathy (beading or narrowing of intracranial cerebral vessels) is the leading cause of childhood stroke. Common features include unilateral stenosis of the large arterial vessels of the anterior circulation, including the distal internal carotid artery and proximal segments of the middle and anterior cerebral arteries, and distinct angiographic appearance with focal, segmental stenosis, often with alternating areas of narrowing and dilation with a “banding” or “striated” appearance. Features of other childhood arteriopathies, such as dissection or moyamoya, are absent. Serial arterial imaging demonstrates progression over days to weeks. This syndrome typically occurs in healthy, school-aged children, and has high recurrence rates and poor outcomes. Indirect evidence that this syndrome is caused by vasculitis includes a temporal association with nonspecific symptoms of infection and imaging markers such as vessel-wall enhancement. However, definitive evidence of an inflammatory pathophysiology cannot usually be obtained, as the affected arteries are not amenable to biopsy and postmortem studies are lacking.

Progressive medium–large-vessel cPACNS is uncommon. The clinical presentation is less acute, typically with longer-standing, nonfocal, diffuse neurological symptoms such as neurocognitive decline, seizures, or headaches. Imaging often reveals multifocal, bilateral parenchymal lesions with multiple, bilateral stenoses of the large vessels on angiography. Long-term surveillance and outcome studies are required to better understand the natural history and predictors of monophasic versus chronic or progressive forms of medium–large-vessel cPACNS.

MRI, MRA, and CTA are the imaging modalities with the highest diagnostic yield when considering CNS vasculitis. Children with medium–large-vessel vasculitis will demonstrate supratentorial, asymmetrical lesions of the white matter or deep gray structures. The presence of multifocal, bilateral, and gray matter lesions, combined with multiple, bilateral, or distal vessel stenosis, are predictors of progressive disease. CTA and MRA can confirm and often characterize arteriopathy in most children with large-vessel disease, providing excellent images of first- and second-order cerebral arteries ( Fig. 31.1 ). Conventional angiography can add additional details while helping to exclude other causes such as dissection or moyamoya. Vascular imaging features suggesting inflammation and large-vessel vasculitis include stenosis or occlusion without evidence of dissection or chronic arteriopathies. Vessel wall enhancement on MRAs performed with gadolinium is also suggestive of vasculitis. Banding or striae may be unique features of medium–large-vessel vasculitis. In medium–large-vessel disease, comparisons of MRA to conventional angiography suggest sensitivity and specificity of 70% and 98%, respectively. Only 71% of children with abnormal conventional angiography had detectable MRA changes of medium–large vessels, emphasizing that conventional angiography is clearly more sensitive and specific than MRA. A newer technique, vessel wall imaging (VWI) MRA technique, including high-resolution anatomical and blood sensitive sequences, may help demonstrate arterial pathology, but this has not been frequently described in children.

Histological evidence of vascular inflammation is the diagnostic gold standard for small-vessel pediatric CNS vasculitis. ^, Biopsies are ideally taken from the brain regions that are involved on MRI, with care to avoid biopsy of critical regions, such as the motor strip or language area. Biopsy yield is influenced by (1) whether T2 bright or enhancing lesions are present at the biopsy site, (2) whether focal meningeal enhancement is present, and (3) whether corticosteroids have been administered prior to biopsy (even 2 weeks of intravenous methylprednisolone can markedly reduce diagnostic yield). Biopsies should be an adequate size (1 × 1 × 2 cm ³ ), include all layers (meninges and gray and white matter), and processing should include a snap-frozen section for electron microscopy ( Fig. 31.2 ). By definition, vasculitis implies direct invasion of one or more layers of the vessel wall by inflammatory cells with hyalinization/destruction of the vascular endothelium. Histopathological findings in cPACNS are distinctly different from adult studies. In small-vessel disease, a nongranulomatous lymphocytic infiltration of small vessels is the most common finding. Microglia activation, often termed microglial nodules, is commonly seen in children with long-standing inflammatory disease but must also be distinguished from chronic infection.

There have been no CNS vasculitis clinical trials to guide the care of children with these disorders. A collaborative network, termed BRAINWORKS , has proposed treatment regimens for children with CNS vasculitis subtypes. These consensus-driven recommendations have not been tested in a rigorous fashion. A regimen for a nonprogressive large-vessel subtype recommends a 4 to 5 month course of prednisone as long as there is no progression on vascular imaging at 3 months. Small-vessel and progressive large-vessel treatment regimens are based on results from the treatment of 19 children with small-vessel disease. The regimen includes 6 months of induction treatment utilizing a combination of prednisone (beginning at 2 mg/kg/day, maximum 60 mg/day, tapering monthly) and intravenous cyclophosphamide (500 to 750 mg/m ² every 4 weeks for a total of seven infusions), along with Pneumocystis jirovecii pneumonia prophylaxis. During the subsequent 18 months, maintenance therapy recommendations consist of low-dose oral prednisone (anticipated prednisone tapering off by 12 to 14 months from the start of induction) and one of mycophenolate mofetil (MMF) (800 to 1200 mg/m ² /day divided twice daily [BID], maximum 2000 mg/day), mycophenolic acid (500 to 800 mg/m ² /day BID), or azathioprine (2 to 3 mg/kg/day, maximum 150 mg/day). Case reports and small case series have described beneficial effects of infliximab, tocilizumab, and intravenous immunoglobulin (IVIG) in both primary and secondary causes of CNS vasculopathy (such as neuro-Behçet) and primary angiitis of the CNS. Given these reports, the BRAINWORKS investigators recommend usage of a 6-month course of infliximab along with IVIG, methotrexate (for dampening of human antichimeric antibody production), and tapering corticosteroids in children refractory to the standard proposed regimen or in children who relapse during treatment. Children with severe relapses may respond to reinduction with cyclophosphamide or to acute administration of infliximab. Treatment of a minor flare (minimal symptoms with new lesions on imaging) may include only corticosteroids, IVIG, and/or resumption of oral agents if not already on them (i.e., MMF or azathioprine).