Aicardi-Goutières Syndrome

AGS is a genetic encephalopathy that often presents as a mimic of congenital infection. The disorder is mediated by mutations in genes related to the removal of infectious or endogenous nucleic acids. The accumulation of nucleic acids is thought to mimic viral infection and trigger activation of Toll-like receptors of the innate immune system, in turn stimulating production of interferon-α (IFN-α) and leading to inflammatory cascades that result in neurologic signs and symptoms. Although the understanding of the molecular and genetic basis of AGS is expanding considerably, the clinical presentation and progression can be divided into 2 main phenotypes: neonatal onset and later onset.

The neonatal form presents with nonspecific features of encephalopathy, and affected neonates may show jitteriness, seizures, and poor feeding that may mimic neonatal sepsis. Findings include hepatosplenomegaly, anemia, thrombocytopenia, and increased transaminase levels. The head circumference, typically normal at birth, may progressively decrease relative to other normal trajectories of growth, although deceleration of head growth can begin in utero. Stagnation and even regression of motor and social milestones become apparent as the child’s irritability persists. This neonatal presentation is reminiscent of TORCH infection or congenital infection with the HIV, although negative TORCH and HIV investigations, as well as the absence of microcephaly, retinopathy, hearing loss, or hydrocephalus, should direct attention to alternative diagnoses such as AGS. The localization of calcifications to the basal ganglia on neuroimaging (as opposed to a more diffuse pattern seen in TORCH infections), the intermittency of fever, and persistence of cerebrospinal fluid pleocytosis despite negative infectious studies are diagnostically important and distinguish AGS from other diseases.

Children with later onset AGS present with subacute progressive encephalopathy as shown by irritability, loss of milestones, slowly progressive microcephaly or head growth deceleration, and episodic fever. On neurologic examination, pyramidal (spasticity) and extrapyramidal (dystonia) signs appear, because optic atrophy or pallor and ocular jerks are evidence of cortical blindness. Vascular necrotic cutaneous lesions (chilblains), hepatomegaly, increased transaminase levels, thrombocytopenia, glaucoma, hypothyroidism, diabetes mellitus, and antidiuretic hormone deficiency are non-neurologic features. Thrombocytopenia, hypothyroidism, and diabetes deserve special mention because they are typically caused by immune thrombocytopenia purpura, autoimmune thyroiditis, and type I diabetes, respectively, and further show the central nature of autoimmunity in this disease.

Diagnosis is supported by showing increased IFN-α and neopterin levels in the cerebrospinal fluid, or by showing an abnormal interferon expression signature on quantitative polymerase chain reaction analysis in peripheral blood mononuclear cells, although these tests are not widely available clinically. Nonspecific cerebrospinal fluid lymphocytic pleocytosis should also be present, but the cerebrospinal fluid cell count and IFN-α signature can be normal, especially in the later stages of the disease after the active encephalopathic phase. Neuroimaging studies may support diagnosis as well. The neuroimaging findings of AGS are typically characterized as having a triad of cerebral calcifications, white matter lesions, and cerebral atrophy. Head computed tomography (CT) scans provide the most sensitive evaluation for cerebral calcifications, which are typically seen within the basal ganglia, lobar white matter, and dentate nuclei. Although cerebral calcifications are considered diagnostic of AGS, they may not be present on an initial CT scan. Head CT scans may also reveal cerebral atrophy and white matter lesions as decreased cerebral volume and hypoattenuating lesions in the white matter, respectively; however, MRI allows better characterization of these findings. The white matter lesions in AGS show increased signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences. More severe lesions also show decreased signal intensity on T1-weighted images. White matter lesions show a lobar predominance with relative sparing of the periventricular, callosal, and capsular white matter and of the optic radiations. The subcortical arcuate fibers are typically involved. Two patterns of white matter involvement have been described: diffuse involvement of lobar white matter and an anteroposterior gradient with more intense involvement in the frontal lobes. White matter disease can progress to cystic lesions, which has been described in the frontal and temporal white matter.

Cerebral Folate Deficiency

Cerebral folate deficiency is characterized by decreased concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid, in the presence of normal blood folate concentrations. The 5-methyltetrahydrofolate deficiency is caused by inadequate transport of folate across the blood-brain barrier caused by decreased function of the folate receptor-alpha. This receptor dysfunction seems to be caused either by mutations in the FOLR1 gene, which encodes the receptor, or by autoantibodies directed against the receptor. If cerebral folate deficiency is promptly and appropriately diagnosed, supplementation with folinic acid can halt progression of symptoms.

The disorder presents after normal pregnancies, deliveries, and neonatal periods with irritability, sleep disturbance, developmental stagnation or regression, and head growth deceleration. Hypotonia, spasticity, ataxia, and refractory seizures may ensue. Visual loss and later hearing loss occur, and some patients develop symptoms of autistic-type behaviors or psychosis.

Diagnosis in the setting of this presentation is supported by showing decreased 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid (typically < 40 nmol/L) in the setting of normal blood folate concentrations. If blood folate levels are reduced, dietary deficiencies and gastrointestinal absorption abnormalities should be excluded, as should systemic abnormalities in folate metabolism, such as methyltetrahydrofolate reductase (MTHFR) deficiency or dihydrofolate reductase deficiency. MTHFR deficiency is suggested by the presence of increased blood homocysteine and decreased blood methionine levels, whereas dihydrofolate reductase deficiency is suggested by megaloblastic anemia or pancytopenia. Specific assays for folate receptor-alpha antibodies are available, and analysis for FOLR1 gene mutations, deletions, or duplications can be performed. Frontotemporal atrophy and periventricular and subcortical demyelination may be noted on neuroimaging, as well as nonspecific white matter lesions that show increased signal intensity of T2-weighted and FLAIR sequences.

The differential diagnosis of cerebral folate deficiency includes methyltetrahydrofolate reductase deficiency, dihydrofolate reductase deficiency, Kearns-Sayre syndrome, Rett syndrome, AGS, 3-phoshoglycerate dehydrogenase deficiency, dihydropteridine reductase deficiency, mitochondrial complex 1 encephalomyopathy, and aromatic amino acid decarboxylase deficiency.

Hemophagocytic Lymphohistiocytosis and the Macrophage Activation Syndrome

HLH is a syndrome of uncontrolled immune activation that causes a picture of disseminated intravascular coagulation and systemic inflammation. Typical children with HLH are acutely ill with fever, irritability, hepatosplenomegaly, and a purpuric rash from disseminated intravascular coagulation, and this presentation is often mistaken for sepsis with multiorgan dysfunction occurring in severe cases. HLH can be either primary and caused by genetic defects in molecules important for cytotoxic granule release in natural killer (NK) cells and cytotoxic T cells, or it can be secondary to infection or to an underlying inflammatory disease such as systemic onset juvenile idiopathic arthritis (SOJIA) or systemic lupus erythematosus (SLE). Secondary HLH associated with an underlying inflammatory disease is referred to as macrophage activation syndrome (MAS) and typically presents less severely and at a later age than primary HLH. Most patients with primary HLH become symptomatic in the first few years of life, although some present at school age or later.

Approximately 50% of affected patients develop neurologic involvement, either as a primary manifestation or later in the course of the disease, with symptoms including irritability, alteration of consciousness, psychomotor retardation, ataxia, spasticity, hypotonia, hemiparesis, seizures, or meningismus. Rarely, HLH presents with isolated neurologic involvement preceding systemic illness by years. HLH has been reported to present with isolated ataxia and cerebellar involvement, encephalopathy, focal neurologic deficits, seizures, mass lesions, and demyelinating lesions. In many cases, patients were treated with steroids for suspected acute disseminated encephalomyelitis, but later relapsed on withdrawal of steroid therapy. HLH must be considered in young patients with neurologic disease without a clear explanation, especially if they show other diagnostic criteria for HLH ( Box 1 ).

Diagnosis of HLH is based on the HLH 2004 guidelines, which require either demonstration of a known genetic cause of HLH or fulfilment of 5 of 8 diagnostic criteria (see Box 1 ). Macrophage activation syndrome can be diagnosed using similar criteria qualitatively, although, in practice, because MAS tends to be less severe, patients with MAS might not meet the strict numeric criteria for HLH. For example, a patient with MAS may be cytopenic relative to their level of inflammation and show a progressive trend downward, but not meet the numeric cutoffs for cytopenia in the HLH 2004 guidelines. This possibility is reflected in the recently published guidelines for diagnosing MAS in patients with known SOJIA, the most common rheumatic cause of MAS. The criteria used in these guidelines are similar to the HLH 2004 criteria, but with less stringent cutoffs for the laboratory criteria.

Imaging findings of HLH are nonspecific and change throughout the course of the disease. CT of the head may show hypoattenuating parenchymal lesions or calcifications, both of which are most commonly located at the gray-white junction. MRI of the brain has a higher sensitivity for parenchymal lesions, which may be supratentorial and/or infratentorial, and may involve the gray and/or white matter with a predominance at the gray-white matter junction. The parenchymal lesions are typically laminated, nodular areas of increased signal intensity on T2-weighted and FLAIR sequences. The laminated signal refers to central increased signal surrounded by a rim of low signal intensity. These lesions may become confluent as the disease progresses ( Fig. 1 ). Postcontrast T1-weighted images may show nodular, linear, or rim enhancement of the parenchymal lesions. Leptomeningeal enhancement may also be seen on postcontrast images but is not present in all cases. Follow-up images may show cerebral atrophy (see Fig. 1 D) and hemorrhage within parenchymal lesions. Imaging findings outside of the CNS can also be seen in children with HLH. Abdominal ultrasonography may show hepatosplenomegaly, gallbladder wall thickening, and ascites.

A 16-month-old boy with hemophagocytic lymphohistiocytosis. ( A ) Axial T2-weighted MR image shows diffuse increased signal intensity throughout the cerebellar white matter ( arrows ). ( B ) Axial postcontrast T1-weighted MR image shows patchy areas of enhancement throughout the cerebellar white matter lesions ( dashed arrows ). ( C , D ) Sagittal T1-weighted MR images obtained at 16 months ( C ) and 22 months ( D ) of age. On the initial MRI ( C ) there was cerebellar swelling ( arrowheads ); on the follow-up MRI ( D ) there is marked cerebellar atrophy ( open arrow ).

Angiography-Positive Primary Angiitis of the Central Nervous System

Primary angiitis of the CNS (PACNS) is an idiopathic granulomatous vasculitis of CNS vessels that presents with focal neurologic deficits, but can also present with seizures, cognitive dysfunction, and behavioral changes. Focal neurologic signs in PACNS stem from ischemia secondary to vessel narrowing or to thromboembolic events from damaged and therefore thrombogenic vascular endothelium. A more diffuse presentation is more likely to occur with angiography-negative PACNS and may be caused by smaller ischemic foci or by vasculitic disruption of the blood-brain barrier with resultant local disruption of neuronal function. Angiography-negative PACNS is discussed in more detail in the context of conditions presenting with encephalopathy.

In children, PACNS is broadly divided into angiography-positive and angiography-negative disease based on findings on conventional angiography, which is the gold standard imaging test. An acute stroke presentation with focal neurologic findings is more likely to occur with angiography-positive disease. In addition, patients presenting with a symptom cluster consisting of paresis, speech difficulties, and imaging findings consistent with ischemia are more likely to have angiography-positive PACNS. Therefore, the initial evaluation of focal neurologic signs should include vascular imaging, usually magnetic resonance (MR) angiography of the brain, along with conventional brain MRI.

More than half of adult patients with PACNS show multifocal infarcts. The findings in children are similar, although multifocal infarcts are more likely to occur unilaterally and affect territories supplied by the anterior circulation, especially the lateral lenticulostriate territory and the basal ganglia. MRI findings in PACNS include areas of high diffusion-weighted imaging signal with associated low absolute diffusion coefficient signal indicating acute to subacute infarction ( Figs. 2 and 3 ). In addition, white matter T2/FLAIR lesions, mass lesions, meningeal enhancement, and hemorrhages can be seen but are less specific for PACNS. If MRI and MR angiography are not diagnostic, diagnosis may require conventional angiography, which has a higher resolution and therefore higher sensitivity for small vessel lesions, but entails higher risk to the patient. Conventional angiography may show segmental irregularity, or narrowing or occlusion of small and medium-sized parenchymal and leptomeningeal arteries. The classic sign on any type of angiography is multiple adjacent areas of focal narrowing giving the appearance of “beads on a string”.

A 15-year-old boy with primary angiitis of the CNS. Axial diffusion-weighted imaging (DWI) ( A ), and apparent diffusion coefficient (ADC) ( B ) sequences from brain MRI at the time of initial presentation. There is a focal area of abnormal signal intensity in the medial, inferior aspect of the left basal ganglia ( solid arrows ) that is increased signal intensity on the DWI and low signal intensity on the ADC sequences, consistent with restrictive diffusion caused by an acute infarct.

A 12-year-old boy with primary angiitis of the CNS. Axial DWI ( A ) and ADC ( B ) sequences at the time of initial presentation show an area within the region of the right external capsule ( arrows ) that is increased signal intensity on the DWI and low signal intensity on the ADC sequences. This finding is consistent with an acute stroke. Axial ( C ) and three-dimensional (3D) reformatted ( D ) images from time-of-flight (TOF) MR angiography (MRA) shows absence of flow within the distal right internal carotid artery ( dashed arrows ). The left internal carotid ( open arrows ) and basilar ( arrowhead ) arteries show normal flow.

Antiphospholipid Antibody Syndrome and Neuropsychiatric Systemic Lupus Erythematosus

APLS is characterized by a propensity for venous or arterial thrombosis or for recurrent miscarriages in the setting of positive serum antiphospholipid antibodies. The syndrome can occur as a primary phenomenon or as secondary to systemic autoimmune disease, usually SLE. Because up to 30% of patients initially diagnosed with APLS go on to develop criteria for SLE, some investigators have suggested that APLS may be a precursor to SLE. SLE is itself a risk factor for clotting and therefore, antiphospholipid antibodies in the setting of SLE can be particularly problematic. Diagnosis of APLS is based on the Sydney criteria ( Box 2 ), which require demonstration of either thrombosis or pregnancy-related morbidity (eg, recurrent miscarriages) and at least 1 laboratory criterion showing antiphospholipid antibodies (eg, lupus anticoagulant, anticardiolipin antibody or anti–β2-glycoprotein antibody).

Neurologic symptoms in APLS arise through several different mechanisms. Arterial thrombosis can lead to transient ischemic attacks and stroke, cerebral venous sinus thrombosis can cause both focal and diffuse neurologic symptoms, and nonthrombotic sequelae have been proposed to be caused by APLS as well. Up to 26% of patients with primary or secondary APLS present with acute arterial ischemic stroke. Acute stroke in APLS presents in a manner similar to strokes of other causes, with focal neurologic symptoms localizable to the thrombosed vascular territory, most often in the anterior circulation, and MRI findings that indicate cerebral ischemia. In the context of SLE, embolic stroke may also occur because of SLE-associated cardiac valvulitis, either alone or in combination with APLS.

Cerebral venous sinus thrombosis is the initial manifestation of APLS in 7% of patients and can present with focal neurologic findings caused by parenchymal lesions, most commonly monoparesis or hemiparesis. Venous sinus thrombosis can also present with more diffuse neurologic findings related to decreased cerebrospinal fluid resorption and increased intracranial pressure, such as headache, vomiting, papilledema, and the Cushing triad. Alternatively, decreased cerebral perfusion pressure can cause diffuse cerebral dysfunction and symptoms of encephalopathy with mental status change, stupor, or coma. MRI of the brain with venography shows reduced flow within the affected sinus ( Fig. 4 ). Ultrasonography can be used in the detection of peripheral venous and arterial thrombosis (see Fig. 4 D). Conventional venography and angiography are still considered the gold standard for the detection and characterization of thrombus and are typically used in cases in which catheter-directed thrombolysis is indicated.

A 16-year-old with lupus and antiphospholipid antibody syndrome. ( A ) Axial TOF MR venography (MRV) of the head shows normal flow in the sagittal sinuses ( solid arrows ). Axial ( B ) and 3D reformatted ( C ) images from TOF MRV performed the following year show lack of flow within the right sagittal sinus ( dashed arrows ) with preserved flow in the right sagittal sinus ( open arrows ). ( D ) Color Doppler ultrasonography image of the left superficial femoral vein (SFV) in the same patient performed shortly after the MRV in B shows lack of color Doppler signal in the SFV consistent with occlusive thrombus. Flow is present in the adjacent superficial femoral artery (SFA).

The other most common findings on MRI in lupus involving the CNS are small focal subcortical and periventricular white matter lesions with increased signal intensity in T2-weighted and FLAIR sequences ( Fig. 5 ). Areas of acute and subacute infarction show increased signal intensity on diffusion-weighted imaging and low signal intensity on apparent diffusion coefficient (ADC) sequences (see Fig. 5 ). Intracranial hemorrhage may manifest as parenchymal hemorrhage, subarachnoid hemorrhage, or subdural hematoma. The appearance of hemorrhage on CT and MRI depends on the chronicity of the bleed. Cerebral atrophy is seen in slightly less than half the patients affected. CT, MR, and conventional angiography may show narrowing or occlusion of the carotid arteries. Coexisting myelopathy is rare in children with CNS involvement of lupus but, if present, shows increased signal intensity within the central spinal cord on T2-weighted MR sequences.

A 15-year-old boy with CNS lupus. ( A ) Axial T2-weighted MR image shows a focal area of increased signal intensity within the right periventricular white matter ( arrow ). Axial DWI ( B ) and ADC ( C ) sequences show that this lesion ( arrows ) has increased signal intensity on the DWI and low signal on the ADC sequences, consistent with restrictive diffusion seen with an acute infarct.

APLS is associated with a variety of nonthrombotic neurologic complications, such as seizures, chorea, transverse myelitis, dementia, migraine, cognitive dysfunction, and psychiatric symptoms, although some of these associations are controversial. Chorea, other movement disorders, and transverse myelitis are particularly associated with antiphospholipid antibodies in the setting of SLE. Some of these manifestations may be related to infarcts that are too small to be seen on neuroimaging, such as multi-infarct dementia or seizures secondary to small infarct-related epileptic foci, although some studies have suggested that antiphospholipid antibodies may target specific neuronal antigens or may simply indicate a propensity for developing CNS autoimmunity. Antiphospholipid antibodies are known to have more subtle effects on endothelial function and it is interesting to speculate that they might be altering the function of the blood-brain barrier.

When nonthrombotic complications of APLS predominate, the disorder may not enter the differential diagnosis; however, subtle systemic findings may reorient the clinician to the possibility of antiphospholipid antibody-mediated disease. Systemic findings suggestive of APLS include livedo racemosa, a lacy or netlike rash similar to cutis marmorata that can occur in approximately one-fourth of patients with APLS. In contrast with the more physiologic cutis marmorata, livedo racemosa associated with APLS has more broken circles, does not resolve as well with rewarming, and does not respond to changes in position. Patients with APLS can also develop vasculopathic lesions and ulcers. In addition, patients with APLS commonly develop thrombocytopenia and autoimmune hemolytic anemia. In patients with thrombotic and nonthrombotic neurologic sequelae of APLS, these findings alert clinicians to the possibility of antiphospholipid antibodies underlying the patient’s symptoms. However, no specific therapy, such as anticoagulation or immune therapy, has been clearly shown to be beneficial for the nonthrombotic manifestations of APLS, and treatment is limited to symptomatic management.