Infantile spasms [30] are types of early childhood seizures characterized by clusters of flexor or extensor epileptic spasms, along with characteristic EEG changes, and progressive neurological development deterioration [31, 32].

The first description of epileptic encephalopathy dates back to Dr. William James West who, in 1857, described the syndrome [32], initially in his own son. The term ‘West Syndrome ’ has been used to indicate infantile spasms, hypsarrhythmia, and cognitive impairment.

The incidence is 0.25–0.4:1000 live births [31]. When not idiopathic/cryptogenic (which is approximately 25 % of cases,) the causes are often similar to the causes of cortical visual impairment, and include hypoxic ischemic encephalopathy , cortical immaturity, congenital abnormalities of the brain or occipital cortex, or neurometabolic and genetic diseases such as Aicardi’s and tuberous sclerosis [33]. When one of these causes is identified, the disease is termed “symptomatic” as opposed to idiopathic or cryptogenic [34].

The first symptoms of infantile spasms are usually manifest during the first year of life, age 6–9 months, paralleling a critical period required for proper maturity of visual pathway, including both retina and the visual cortex [35]. The child develops infantile spasms and then progressive deterioration of cognition, and disruption of cortical bioelectrical activity. With this disruption of cortical activity comes cortical impairment and associated vision loss.

A maturation defect of fixation shift skills is generally observed in infants with infantile spasms, often paralleling a cognitive deterioration, several weeks before the onset of spasms [36]. This decrease in visual attention is separate from the cortical vision loss described in the systemic manifestations section, which these patients can also experience [33].

Clinically, one suspects infantile spasms by parental history or observation of the event. Hypsarrhythmia is seen between seizures, and is characterized by a high voltage (>300 μV), disorganized electrocerebral background with multifocal spikes [37]. The spasms also have a characteristic EEG appearance.

Workup for a metabolic or genetic cause is indicated in cases that do not have other identifiable abnormalities on imaging. A large number of inborn errors of metabolism have been identified in the setting of infantile spasms. These include, but are not limited to, biotinidase deficiency, pyridoxine deficiency, mitochondrial disorders, Menkes Disease, congenital disorder of glycosylation type III, phenylketonuria, peroxisomal disorders, and lysosomal disorders [37]. Defects in a variety of genes have likewise been reported.

As with other seizure disorders, AEDs are the mainstays of treatment. See the special section on Vigabatrin below, as ACTH or vigabatrin are first line for infantile spasms . The ketogenic diet has also been used.

Vigabatrin is a gamma-aminobutyric acid (GABA) analog that inhibits GABA transaminase. It has been approved for use in the US as an antiepileptic drug (AED) since 2009 [38], and is typically used as adjunctive therapy for adult patients with refractory complex partial seizures, or as monotherapy for infants with infantile spasms, especially in those patients with tuberous sclerosis [39]. Unfortunately, an irreversible, bilateral constriction of the visual fields from retinal toxicity can occur with vigabatrin use.

This adverse reaction to the drug was first reported in 1997, and since then many other studies have illustrated similar visual field loss with reproducibility [40].

Visual field loss has been found in approximately one half of adults and one third of children treated with vigabatrin [39].

Vigabatrin can cause fatigue. There have been some associated MRI changes of unknown significance, as well.

The onset of visual field loss tends to occur in the first few years after starting vigabatrin [39]. Initially believed to remain stable in early studies, the deficits seem to slowly progress with continued vigabatrin exposure, as demonstrated in a 10-year follow-up study [41]. The deficits are typically not self-recognized early on because they relatively spare the macula, but there is electrophysiological evidence of decreased macular function. Visual field loss is probably correlated with cumulative dose, but individual variation is not uncommon [42].

The mechanism for the retinal toxicity associated with vigabatrin-induced visual field loss is uncertain. However, there is some evidence that vigabatrin induces a taurine deficiency in retinal photoreceptors that leads to phototoxicity [43]. These patients also can show associated thinning of the retinal nerve fiber layer (RNFL) [44–46]. The risk to the developing retina from vigabatrin exposure in utero is unknown [10].

The Food and Drug Administration has recommended eye examinations and visual field tests every 3 months because automated static perimetry is the most sensitive test for the detection of early visual field changes. In children who require vigabatrin, however, this can be quite difficult, as perimetry requires active cooperation of the patient, and typically successful perimetry requires a developmental age >9 years [47]. Kinetic perimetry may be considered over automated static perimetry, as the latter may produce variable results in patients with epilepsy [47]. Perimetry is excellent for diagnosis and detection of visual field loss in the cooperative, older patient, but they are imprecise and insensitive in younger children and children with neurological impairment. Inconclusive tests are frequent, reproducibility is poor, and many patients are untestable, which is part of the reason that prevalence of visual field loss in children seems to vary considerably from one study to another [48].

A number of alternative objective tests have been proposed to this end, including serial electroretinograms (ERGs) , optical coherence tomography (OCT) , visual-evoked potentials, and serial fundus examinations [49]. OCTs may demonstrate thinning of the RNFL and are suggested as alternative for young patients who cannot perform perimetry but this test also has practical difficulties in children [42, 46]. ERGs can be very difficult to interpret in these patients and all of these tests may be of minimal value, if any, in the detection of early field changes [50]. As it stands, there is currently no simple, effective method to screen for vigabatrin-associated visual field deficits in many younger or neurologically impaired children .

Regular, age-appropriate vision testing is considered critical, starting with baseline testing and every 3 months during therapy, as well as 3–6 months after discontinuation [42]. Also the ongoing need for treatment with vigabatrin should be periodically reconsidered [47], and the lowest effective dose of the drug should always be used.

Concussion is a result of head trauma that causes transient disruption of brain function through concussive forces leading to neurologic symptoms [56].

Estimates show that nearly 150,000 children and adolescents are seen in emergency departments for concussion each year [57].

Many physicians in history have written about and described what is now known as concussion. The corpus Hippocraticum , dating back to the fourth and fifth century, BC, contains references to cerebral concussions, which were translated as commotio cerebri —“caused by a blow, the victim loses his speech and cannot see or hear [58].”

Higher function problems include difficulties with attention, memory, and concentration. One study showed that headache, fatigue, and dizziness were most common at initial presentation and sleep disturbance, frustration, and forgetfulness developed after the initial injury.

Ocular symptoms may include diplopia, blurred vision, transient loss of vision and visual processing problems. One may see abnormalities in saccade generation, pursuit, convergence, and accommodation [56]. All of these can cause difficulty with reading. Ocular symptoms resolved faster than the other symptoms listed, which can last anywhere from 2 weeks to more than 3 months [59]. More permanent injuries would include 4th nerve palsy or traumatic optic neuritis .

The diagnosis of a concussion is based on the history of recently having an injury to the head or neck with any resultant neurologic symptoms. Sideline assessment tools such as the Post-Concussion Symptom Scale (PCSS) and Graded Symptom Checklist (GSC) can be useful for trainers and coaches at sporting events. These tests are not used to rule out concussion, however. The child should be taken out of the game and if there are any persistent symptoms, medical care should be sought immediately to check for any abnormal neurologic signs. CT should not be used to diagnose concussion but should be used to evaluate hemorrhage or fractures if there is clinical suspicion [60]. If there are focal neurologic signs, imaging with an MRI should be done emergently, along with consultation with Neurology.

Treatment is symptomatic for the patient’s specific manifestations, which can include headaches, visual disturbances, nausea, sleep difficulties, and mood lability. Though most symptoms improve with time, repeated concussions can cause more severe symptoms that take longer to resolve. The effects are often cumulative, with frontal and temporal lobe damage as shown on histopathology [56]. Athletes should not return to play until they have been cleared by their physician. A step-wise approach with monitoring for any recurrence of symptoms is best.

Papilledema is the swelling of the optic disc as a consequence of increased intracranial pressure. Initially, there is interstitial edema in the optic nerve. This is followed by axoplasmic stasis and neuronal dysfunction that lead to vision loss [61].

Idiopathic intracranial hypertension can occur in children and adults and is defined as elevated intracranial pressure that is not explained by another cause.

Sir John Herbert Parsons, a British Ophthalmologist, first coined the term “papilledema” in 1908 to refer to optic disc swelling associated with increased intracranial pressure [62].

Heinrich Quincke reported the first recorded cases of intracranial hypertension of unknown cause in what he described as “meningitis serosa” in 1893 [63]. The term “pseudotumor cerebri ” was coined in 1904 by Max Nonne [64].

Idiopathic intracranial hypertension is most common among obese women between 20 and 40 years of age, but it can occur in all age groups and genders. It is reported to occur in 1 in 100,000 individuals [65]. In the pediatric population, studies have shown that there is no gender predilection prior to puberty , there is less of an association with obesity than in adults, and more frequently, secondary causes exist [66, 67].

Headache is the most common symptom [68]. Other symptoms can include pulsatile tinnitus, or vomiting. Patients may experience headaches that are worse in the morning, while laying down, after exertion or vagal maneuvers, or those that wake them up from sleep.

Patients can experience transient visual obscurations, blurred vision, and decreased color vision . Optic atrophy can also occur from severe or long-term papilledema. Cranial nerve 6 may be affected secondary to mass effect from elevated intracranial pressure , causing esotropia and diplopia [69].

The differential diagnosis of optic nerve head swelling with elevated intracranial pressure includes hydrocephalus from congenital hydrocephalus, brain tumor, meningitis, craniosynostosis, idiopathic intracranial hypertension, and leukemic infiltrate. Key findings on physical exam include a bulging fontanelle in an infant or abnormal head shape suggestive of craniosynostosis . Optic disc swelling that mimics papilledema but is not due to elevated intracranial pressure may be caused by inflammatory, vascular, or autoimmune etiologies, or may be pseudopapilledema, which can be from optic nerve drusen.

On clinical exam, initially vision, color vision , and pupils can be normal, but these will become abnormal if the papilledema is severe or chronic. Acute papilledema will present with obscuration of the optic disc border, elevation of the entire optic nerve, obliteration of the optic nerve cup, with or without retinal hemorrhages. In severe cases, there can be nerve fiber layer edema and infarction, and the swelling can extend into the retina, including the macula, causing circumferential retinal folds (Paton’s lines), or hard exudates in the form of a macular star. Often, the retinal vessels are engorged and tortuous.

Chronic papilledema can present with optic nerve pallor, hard exudates, and retinal nerve fiber layer atrophy, and can have decreased vision and visual field changes. A cautionary note is that an atrophic nerve that has been damaged from chronic insult may not appear swollen at all, even in the setting of elevated ICP.

Recommended testing includes neuroimaging with an MRI and MR venogram (MRV) . If these studies do not reveal any etiology for the increased ICP, such as a mass or venous sinus thrombosis, the patient should then have a lumbar puncture (LP). This should be done to measure opening pressure with other appropriate CSF tests, including cell count and differential, glucose, protein, and cytology. Other labs, including serum Vitamin A level and thyroid studies can be sent depending on clinical suspicion. Vision, color vision , fundus exam, and visual field testing are necessary to monitor progression of disease .

Management is aimed at treating the underlying cause and to decrease intracranial pressure. Treatments may include therapy or surgery for the underlying tumor, infection, or skull abnormalities, or cessation of medication that causes elevated intracranial pressure (including Vitamin A analogues, tetracycline, and steroids).

In the case of idiopathic intracranial hypertension, the goal of treatment is to reduce intracranial hypertension to preserve optic nerve function, and manage headaches. Weight loss is recommended if the patient is obese. Acetazolamide can medically reduce elevated intracranial pressure. Other medications that have been tried include furosemide and steroids, although steroids paradoxically can also cause idiopathic intracranial hypertension. Repeated lumbar punctures might be necessary to reduce the intracranial pressure if it recurs. Rarely a ventriculoperitoneal or lumboperitoneal shunt may be needed for long-term treatment of both papilledema and headaches. In severe cases, optic nerve sheath fenestration may be indicated, but it does not treat headaches. Papilledema typically resolves within weeks to months after the underlying cause is treated. Rarely, papilledema may resolve in days.

To be discussed in neurocutaneous chapter, along with neurofibromatosis.

Aicardi syndrome is a neurodevelopmental disorder with complete or partial agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms [115].

Of the acute neuromuscular disorders known to affect children, Guillain-Barré (specifically the Miller-Fisher variant) has been known to have ocular manifestations.

Guillain-Barré syndrome (GBS) is an inflammatory demyelinating polyneuropathy characterized by acute, typically bilateral limb weakness and loss of deep tendon reflexes. It is an autoimmune disorder and presents after an infectious illness, most commonly Campylobacter jejuni , a gram-negative bacterium that causes enteritis. Less commonly, other bacteria and viruses have been implicated such as cytomegalovirus, (in up to 10 % of cases [122, 123]), also Haemophilus influenza , Mycoplasma pneumoniae , Epstein–Barr virus and varicella zoster virus [124].

GBS is often used as an umbrella term describing a heterogeneous group of subtypes, including the Miller-Fisher Syndrome variant (MFS). Patients with classic GBS develop a bilateral ascending flaccid paresis in two or four extremities, with variable involvement of bulbar, cervical, facial, and upper limbs, with or without paresthesias. The MFS variant of GBS is specifically characterized by the triad of ophthalmoplegia, ataxia, and areflexia.

There is overlap between the subtypes and variants. Bickerstaff’s brainstem encephalitis, defined by the presence of either altered consciousness or hyperreflexia in addition to progressive ophthalmoplegia and ataxia, is often on the differential for acute onset of ophthalmoplegia [125].

About two thirds of GBS cases are preceded by either diarrhea or upper respiratory infection, but less than 1 in 1000 individuals who have a C. jejuni infection go on to develop GBS [126]. Because only a minority of infected individuals develop the disease, genetic factors may potentially confer susceptibility [126]. GBS is therefore considered to be a complex multifactorial disorder with both genetic and environmental factors.

The MFS variant is more common among patients in eastern Asia, accounting for approximately 20–25 % of cases of GBS [127], compared to the United States where reportedly about 5 % of GBS cases are MFS [128].

The syndrome was named after the French physicians Guillain, Barré, and Strohl, who first described it in 1916, although a variant had been described by Landry as early as 1859. This is the reason it has also been called Landry’s paralysis . In 1932, the triad of ataxia, areflexia, and ophthalmoplegia was first described as a variant of the Guillain-Barre syndrome by J. Collier. However it was not until 1956 that Charles Miller Fisher reported three patients with ataxia, areflexia, and ophthalmoplegia as a separate entity, and thus the Miller Fisher variant was named after him [129].

The patient will often have a history of a recent gastrointestinal or upper respiratory illness, predating the onset of symptoms as short as 3 days or as long as 6 weeks, with a median time interval of 10 days [124]. The patient may complain of numbness, paresthesias, dysesthesias, and/or weakness of extremities that progressively worsens over several days, and may also complain of facial weakness or diplopia depending on the subtype. Classically the limb weakness begins more distally and progresses proximally, termed an “ascending paralysis.”

In the majority of patients, the GBS continues to progress for up to 1–2 weeks after the onset of symptoms. Approximately two thirds of patients have such severe distal limb involvement that they are unable to walk at the peak point in the illness , while 25 % progress to have involvement of the respiratory muscles causing respiratory insufficiency, sometimes requiring intubation [122]. Patients with the MFS variant typically have a more benign course, with 5 % progressing on to develop respiratory insufficiency [130]. The symptoms then resolve at variable rates, making prognostication difficult.

The MFS variant (ophthalmoplegia, ataxia, and areflexia) is the subtype to most likely present with ocular manifestations. The classic ophthalmoplegia is a symmetric paresis of upgaze and progressive impairment of horizontal gaze, with variable involvement of downgaze [131]. Ptosis is typically very mild or not present at all and pupillary dysfunction is variable [131]. There are often asymmetries between the eyes, and a variety of other ocular problems can be found including abduction, adduction, or third nerve palsies , abnormal pursuit, Optokinetic reflex (OKR), vestibulo-ocular reflex (VOR), and VOR-cancellation [125, 132]. Rare reports have also documented nystagmus of various kinds (gaze-evoked, dissociated abducting, convergence-retraction, rebound, and upbeat lid nystagmus) [131].

Several diagnostic criteria for GBS have been proposed, including the recent Brighton Criteria (formed by the Brighton Collaboration, sponsored by the World Health Organization), which proposes various clinical findings, each with a related level of diagnostic certainty. The more findings that are present the higher the likelihood of the GBS diagnosis, helping to account for the syndrome’s heterogeneity and subtypes. It includes the following findings: bilateral and flaccid weakness of limbs, decreased or absent deep tendon reflexes in weak limbs, monophasic course and time between onset-nadir 12 h to 28 days, CSF cell count <50/u, CSF protein concentration > normal value , nerve conduction study findings consistent with one of the subtypes of GBS, and absence of alternative diagnosis for weakness.

A lumbar puncture is typically performed to rule out infectious or malignant causes, and also can support the diagnosis by demonstrating albumin-cytologic disassociation in the cerebrospinal fluid. Of note, however, only 50 % will show this classic albumin-cytologic dissociation during the first week of illness, and only 75 % by the third week of illness. Therefore the absence of albumin-cytologic dissociation does not rule out the diagnosis of GBS. Nerve conduction studies may show prolonged distal latencies , conduction slowing, conduction block, absent F waves, and temporal dispersion of compound action potential in demyelinating cases. They can be helpful to confirm a diagnosis but they are not necessary for diagnosis .

Management is largely supportive. Intravenous immunoglobulin (IVIg) or plasmapheresis can be used in the acute phase. Steroids do not affect the course of the disease [130].

Other neurological conditions, which commonly mimic GBS variants include: brainstem stroke, myasthenia gravis, botulism (described more often as descending paralysis), lyme disease, tick paralysis, and bacterial, carcinomatous, or lymphomatous meningitis [133].

Myasthenia Gravis (MG) is an autoimmune mediated disorder of the neuromuscular junction that results in weakness and fatigue of skeletal muscles. Autoantibodies directed against the Acetylcholine receptor (AChR) or Muscle-Specific Kinase (MUSK) block the transmission of nerve impulses to muscles and prevent the appropriate muscle contraction from occurring.

MG occurs in all ethnic groups and both genders, and while it may occur at any age from infancy to late adulthood, the onset in childhood is less common and accounts for only 10–15 % of cases [76]. When the classic disease does present in children, it is called juvenile myasthenia gravis (JMG) , and the manifestations are the same as those in adults. In post-pubertal children, JMG is more prevalent in females, but in pre-pubertal children the incidence is the same between girls and boys [76].

JMG should not be confused with neonatal myasthenia gravis or congenital myasthenic syndrome .

In transient neonatal myasthenia gravis, a fetus may acquire immune proteins (antibodies) via placental transfer from a mother affected with myasthenia gravis. Between 10 and 25 % of babies born to mothers with MG may have this temporary form of the condition. Generally, the child’s symptoms resolve within weeks to months after birth [134]. Treatment is still important in these cases, as the neonate may be very ill during this period.

Congenital myasthenic syndrome is a similar but different disease of the neuromuscular junction that is genetic rather than autoimmune in origin. It is rare, and rather than being autoimmune in nature, it is caused by genetic mutations that produce abnormal proteins leading to defective acetylcholine, acetylcholinesterase , or the acetylcholine receptor [134].

MG was first recognized as a distinct clinical entity in 1672 by Oxford physician Thomas Willis. His report, which was in Latin, went largely unnoticed, and subsequently the first modern description was made in 1877 by Samuel Wilks, a London physician [135].