Management of pediatric post-infectious neurological syndromes

ADEM is an immune-mediated inflammatory demyelinating disorder that primarily affects brain and spinal cord white matter and in a minor way the gray matter. In 2007, International Pediatric Multiple Sclerosis Society Group (IPMSSG) published consensus definitions for demyelinating disorders of childhood, including ADEM, last updated in 2013 [9]:

The estimated annual incidence of pediatric ADEM is 0.23 to 0.4 per 100.000 children [10].

Male to female ratio is between 1.2–2.6:1 [11]. Most of pediatric ADEM cases are reported to be preceded by systemic viral infections [12]. Vaccination has also been reported to precede ADEM [13]. Histologically, it is characterized by inflammation and perivenous demyelination without axonal damage [14].

The latent period between viral infection and onset of symptoms is typically about 2 weeks [15].

The acute onset may be characterized by fever, lethargy, headache, vomiting, multifocal and self-limiting neurological deficits [16].

Encephalopathy is the hallmark of ADEM, ranging from changes in behavior to coma. The most useful radiological investigation for studying ADEM is MRI: multifocal, hyperintense in FLAIR or T2-weighed lesions are appreciated at cerebral MRI, localized in supra or infratentorial region of the white matter. Gray matter is frequently involved, especially basal ganglia and thalami. Spinal cord MRI can highlight intramedullary lesions involving multiple segments with varying contrast enhancement [9].

ADEM can have a monophasic (more frequent in children), recurrent or multiphasic trend. In the monophasic or classic variant, the clinical event is unique and there are no other demyelinating episodes in history. In the recurrent variant, a new episode of ADEM occurs after at least 3 months from the first event or at least 1 month after the end of steroid therapy, there is no involvement of new clinical and neuroradiological areas and MRI does not show new lesions, but enlargements of previous lesions are possible. In the multiphasic variant, a new episode of ADEM occurs after at least 3 months from the first event or at least 1 month after the end of steroid therapy, it involves new clinical and neuroradiological areas, while showing partial or total resolution of the first lesions [17].

Clinical syndrome characterized by encephalopathy preceded by prodromal symptoms such as fever, cough, vomiting and diarrhoea. Neurological symptoms include consciousness disorders, speech impairment, behavioural changes, visual disturbances, ataxia, asthenia, ophthalmoplegia, paralysis of the facial nerve and headache [18‐20].

MERS has as its principal target the corpus callosum, which is the largest bundle of nerve fibres presenting projections to the prefrontal, premotor, primary motor and primary sensory cortical areas. Consequently, an injury involving these connections justifies the symptomatic picture reported above. MRI shows a transient slightly hyperintense lesion in T2-weighted sequences, isointense or slightly hypointense in T1-weighted sequences. There is also a reduction in diffusion without contrast enhancement. Based on the distribution of the lesions, two types of MERS can be distinguished: reversible splenial lesion only (Type 1) and splenial combined with symmetrical white matter lesions (Type 2) [21, 22].

Electroencephalogram (EEG) abnormalities can also be detected, especially diffuse slow waves. Clinical improvement occurs after 1–2 days, radiological improvement from 10 days up to 4 months. ADEM and MERS are very similar syndromes; however, differences in MRI may be documented: ADEM lesions are asymmetric, do not demonstrate a diffusion restriction and persist for months despite clinical resolution [23].

CIS identifies those demyelinating pathologies that cannot be traced back to the other categories.

It represents a heterogeneous clinical picture of acquired demyelinating diseases that can evolve in both a monophasic and multiphasic trend. Histopathological findings demonstrate lesions very similar to those of Multiple Sclerosis and characterized by an important perivascular and parenchymal inflammation with many T lymphocytes (CD8 > CD4), few B lymphocytes and other plasma cells, in addition to a different number of macrophages/microglia. Other specific features are confluent demyelination with active signs of remyelination, acute axonal damage limited to the demyelinating lesion and astrocytic activation [24].

Clinically CIS can show monofocal or multifocal neurological signs and symptoms in the absence of encephalopathy, with acute or subacute onset.

In particular: optic neuritis, myelitis, supratentorial syndrome (focal neurological signs, behavioural alterations), brain stem syndromes or multifocal symptomatology.

Radiological pictures present “dissemination in space” but no “dissemination in time”. “Dissemination in space” requires more than one hyperintense lesion in T2-weigthed sequences in at least two of the 4 typical sites of Multiple Sclerosis (periventricular, juxtacortical, infratentorial or spinal cord). “Dissemination in time” requires new T2-hyperintense lesion when compared to a previous baseline MRI scan or simultaneous presence of a gadolinium-enhancing lesion and a non-enhancing T2-hyperintense lesion on any MRI scan [2].

While CIS is commonly defined as a prelude to an inflammatory CNS disease without MS criteria, radiological isolated syndrome (RIS) is a controversial entity discovered incidentally on MRI [25]. In literature, 30–40% of RIS patients evolved to CIS or MS [26‐28].

The absence of a clear definition makes its diagnosis, treatment and prognosis very difficult [29].

Among all autoimmune encephalitis, autoimmune encephalitis associated with NMDA-R is the only one that occurs mainly in children and that is related to any infectious events. This is a severe but treatable disease, associated with the presence of direct IgG against GluN1 subunit of the N-Methyl-D-Aspartate receptor in CSF [30].

Clinically, it presents with psychiatric manifestations and neurological deficits such as language alterations, motor disorders, autonomic dysfunctions and alteration of consciousness. CSF analysis often shows pleocytosis and less frequently oligoclonal bands. This indicates that normal CSF tests does not exclude autoimmune encephalitis. In most cases it is possible to find out autoantibodies in CSF, less frequently in serum. MRI can show hyperintense lesions in T2-weigthed sequences or generalized encephalopathy, but it is more frequently normal. In most affected patients, the whole EEG can demonstrate diffuse or focal slow waves or epileptiform changes [31, 32].

It is a rare fulminant and potentially fatal neurological syndrome. It arises in healthy children after an infectious episode with a typical symmetrical involvement of thalami, brain stem and cerebellum. Clinically, it is characterized by a rapid progression of neurological symptoms: deterioration of consciousness, seizures and brain stem dysfunctions. In most cases it is a sporadic and non-recurrent manifestation; however, some recurrent familial cases have been reported due to RANBP2 gene heterozygous pathogenic variants, which are inherited in an autosomal dominant manner. Albeit this genetic condition’s penetrance is known being incomplete and age-dependent, up to the 40% of these individuals will manifest an episode of acute necrotizing encephalopathy. Pleocytosis is not described but an increase in proteins is possible. MRI shows a large hyperintensity in T2-weighted sequences and in FLAIR sequences, a diffusion restriction in DWA/ADC sequence (Indicating cytotoxic oedema) and bleeding. Brain stem injuries are divided into three groups based on signal strength and extent: no injury, mild injury and marked injury [33].

PINS first-line treatment is represented by steroids: intravenous methylprednisolone at dosage of 20–30 mg/kg for 3–5 days followed by oral prednisone 1 mg/kg/day for 1–4 weeks if there is no complete resolution with parenteral therapy, but many studies recommend continuing oral therapy for a total of 3 months [34]. Spinal cord, peripheral involvement and recurring forms appear to correlate with a worse response to steroids. In those cases where steroid therapy is contraindicated or is ineffective, intravenous immunoglobulins 2 g/kg can be used within 2–5 days [34]. As last option, plasma exchange can be used with 5–7 exchanges over 10–15 days, but it is a highly invasive therapy that exposes patient to many risks [34]. In case of autoimmune encephalitis, immunotherapy with cyclophosphamide or monoclonal antibodies can be administered [5].

Classic ADEM variant has an excellent prognosis in the majority of cases, without neurological sequelae or progression towards Multiple Sclerosis. About 32–50% of CIS evolves into Multiple Sclerosis [35].

Type 1 MERS have an excellent prognosis while type 2 MERS can present more frequently neurological sequelae or lack of radiological resolution [23].

Autoimmune encephalitis is a rare and debilitating disease. Altered consciousness, Intensive care unit admission and delay of immunotherapy are associated with poor prognosis, but the absence of heterogeneous studies at this time is an important limiting factor for autoimmune encephalitis prognosis evaluation [36].

Concerning Necrotizing encephalitis, brain stem lesions are associated with a worse prognosis due to respiratory failure, cardiac arrest and neurogenic pulmonary oedema. Mortality rate is about 30%, especially in the first week. The majority of surviving patients have neurological outcomes, including intentional tremor, ataxia, hemiparesis, dysarthria, visual disturbances; less than 10% do not show any sequelae [23].

A PINS diagnosis may be difficult due to the absence of any recognized guidelines and criteria and a specific definition. Aim of this study is to elaborate a diagnostic guide to make a correct PINS diagnosis when referring to a group of conditions who share some specific characteristics in term of clinical and imaging pathways.

PINS diagnosis is based on the recognition of peculiar characteristics of each clinical-radiological category through blood tests (blood count, antibody dosage), CSF analysis (pleocytosis, oligoclonal bands, antibody dosage), MRI (hyperintense lesions in T2-weighted sequences), EEG (slow waves).

Non-specific informations often obtained from laboratory and radiological tests, in addition to low incidence of these Syndromes, contribute to make PINS diagnosis a difficult challenge to face with by clinicians.

A total of 39patients were evaluated in the study period. Of those, 13 patients with significant neurological comorbidities were excluded.

The final sample included 26 patients: 14 males and 12 females (M:F = 1:16); the mean age was 5 years (range 3 months - 13 years). Most of our patients was aged between 1 and 5 years old (50%); a percentage of 8% was younger than 1 years old; a percentage of 23% was between 5 and 10 years old; a percentage of 19% was between 10 and 14 years old. There was no onset seasonality observed but a slight prevalence in spring and winter season was detected (42 and 31% respectively).

Prodromal illnesses were documented in a percentage of 85% (22 patients) with the majority of these being gastrointestinal symptoms or nonspecific febrile illnesses. Four patients (15%) had no clear prodromal illness. Neurologic symptoms developed over 1 to 35 days.

Considering timing between any infectious episode documented and neurological symptoms onset, we evaluated:

Most of our study population had encephalitis at onset.

Clinical features of our sample were evaluated. In particular, visual disturbances, motor symptoms, ataxia, seizures, speech disorders, altered consciousness, headache, psychomotor agitation and neck stiffness were examined. The presence of fever, vomiting and cough have also been studied.

Alteration of consciousness was present in a percentage of 62% (16 patients) with somnolence and bradipsychism.

Motor disturbances were observed in 16 patients (61%): walking deficit and/or sitting posture difficulty and strength deficiency; automatisms, reduced osteotendinous reflexes, intentional tremor, hypertonia and decerebrate posture (flexion of the upper limbs and extension of the lower limbs), were the most detected symptoms/signs.

Ocular disturbances were clinically manifest in 54% (14 patients). They included: visual deficiency and photophobia; deviation of the gaze, strabismus, diplopia, nystagmus, hypo-reactive pupils and papilledema.

Fever was detected in a percentage of 42% (11 patients).

Speech disturbances were observed in 35% of cases (9 patients). They included: dysarthria, slow speech and no speech.

Headache was observed in 23% of cases (6 patients).

Seizures were present in 19% of cases (5 patients). They included: febrile seizures, tonic-clonic seizures and absences. Ataxia was present in 12% of cases (3 patients). Irritability and psychomotor agitation were present in 15% of cases (4 patients). Neck stiffness was present in 8% of cases (2 patients). Vomiting and cough were detected in 19 and 4% of cases (5 patients and 1 patient respectively). They were considered part of the infectious episode concomitant or immediately preceding the neurological disease onset.

The majority of our population had a diagnosis of parainfective encephalitis (46%, 12 patients); ADEM has been identified in a percentage of 30% (7 patients); CIS and MERS have been identified in a percentage of 8% respectively while autoimmune encephalitis and necrotizing encephalitis occurred in a percentage of 4% respectively.

Considering sequelae, motor deficits and cognitive deficits occurred in a percentage of 42 and 25%, respectively. Other sequelae reported have been visual disturbances and seizures in a percentage of 17% respectively (Fig. 1).

An evidence of inflammation is frequent in PINSs. In particular, an elevation of the white cell count in the blood occurred in 25% of patients (mean 12.2 × 10⁹/l, range 3.5–79.3 × 10⁹/l, DS 15). Neutrophils were elevated in 37.5% of patients (mean 6.5 × 10⁹/l, range 1.3–24.6 × 10⁹/l, DS 5.4). By contrast, the lymphocyte count was elevated only in one patient, and 25% of patients had lymphopenia.

The C-Reactive Protein (CRP) (normal values: 0–0.5 mg/dl) was altered in a percentage of 54% with a mean value of 3.6 mg/dl (range 2–20 mg/dl).

Blood cultures were evaluated in 50% of patients with negative results for relevant pathogens.

CRP, IgG and IgM for pathogens were evaluated in 24 patients: a percentage of 58% had at least one positivity (14 cases). In particular, blood RCP showed: Epstein Barr (EBV) positive in 25% (6 cases), with a number of copies/ml between 173 and 65.040; herpes virus 6 (HHV6) positive in 21% (5 cases) with copies between less than 500 and 2289/ml; cytomegalovirus (CMV) positive in 8% (2 cases) with copies between 877 and 86,520/ml.

There were 3 cases of co-infection (12.5%). IgM and IgG for specific pathogens were performed in 19 patients: IgM were positive in 32% of cases (6 patients), revealing the presence of anti-VCA for EBV, anti CMV, anti HHV6, anti-varicella zoster (VZV) and anti-herpes simplex 1/2(HVS 1/2).

Otherwise, IgG were positive in 15 patients (79%): EBV anti-VCA and -EBNA, anti-CMV, anti-HH6, anti-VZV and anti-HSV 1/2 were the most detected.

A CSF chemical analysis was performed in all patients.

The majority of our sample had a clear appearance (92% of cases). CSF was colorless in a percentage of 89% (23 cases), slightly blood in a percentage of 8% (2 cases) and xanthochromia was found in a percentage of 4% (1 case).

Considering CSF cell count: normal CSF count was detected in the majority of the study population (58% of patients, 15 cases); CSF cell count lower than 50/mm³ was found in a percentage of 19% (5 patients); CSF cell count higher than 50 / mm³ was observed in a percentage of 23% (6 cases) (range 1–180 mmc; median 5; DS 46.70). White cell count was normal in the majority of our sample; otherwise, the highest detected value was 420 mmc.

Glucose CSF was within normal limits in all patients. CSF Proteins levels were normal in the majority of the sample population (85% of cases, 22 patients). In particular, the observed highest protein value was 92 mg/dl (range 12–92 mg/dl; median 25.94 mg/dl; mean 33.28 mg/dl; DS 21.61).

Microbiological CSF culture was performed in 18 patients: none pathogens have been detected.

Viral CRP on CSF was performed in 22 patients: it was positive only in one patient for HHV 6 having less than 500 copies/ml.

Oligoclonal bands were positive in 2 patients.

MRI was performed in 24 patients.

The majority of the study population showed MRI alterations (91%, 22 patients): gray matter, white matter, brain stem, optic nerve and cerebellum alterations were detected.

In particular, the gray matter was compromised in a percentage of 62.5% of patients (15 cases); the alterations were mostly widespread, symmetrical or not, involving the basal ganglia, the thalamus and the cerebral cortex. The brainstem was compromised in a percentage of 42% of patients (10 cases) with involvement of the periaqueductal gray matter of the midbrain, pons and medulla oblungata. White matter was involved in a percentage 62.5% of patients (15 cases), showing superficial pathological changes in 33% of patients (8 cases) with diffuse subcortical alterations; a deep involvement was found in a percentage of 58% (14 cases): the semi-oval centers, the internal capsule, the periventricular area, the cerebral peduncles, the corpus callosum and the radiated crown were the structures mostly affected.

Other MRI lesions were observed in cerebellum (25%, 6 patients), optic nerve (4%, 1 patient) and dorsal spinal cord (2 patients). Figure 2 summarizes the results.

Further examinations have been performed: MRI spectroscopy revealed metabolic disturbances in a percentage of 17% of patients (4 cases) showing reduction of noradrenaline and creatine and higher levels in choline and lactate; EEG was characterized by slow waves in two patients; evoked visual potentials were pathological in one case, with an increased latency; computed tomography (CT) was relevant in only 2 cases, showing right cerebellar tonsil through foramen magnum and brain edema.

Antibiotics were given in the majority of our population (73% of patients, 19 cases). In particular, third generation cephalosporin were the most used. Acyclovir was administered in a percentage of 54% of patients (14 cases).

Steroids were used in 73% of patients (19 cases). High dose intravenous methylprednisolone (10–20 mg/kg/die for 3–5 days) was used in a percentage of 57.7% (15 patients). Four of these patients subsequently received a tapered course of oral prednisone. Two patients received only oral dexamethasone and two children received only oral prednisone. Gammaglobulin at doses of 2 g/kg over 2 days was used in a percentage of 30% (8 cases). Plasma exchange was used only in one patient.

We suggest diagnostic criteria for a correct diagnosis of PINS. In particular, we have to consider the following parameters: neurological symptoms, timing of disease onset, blood and CSF laboratory tests, MRI imaging.