WHAT IS IT?

            It is an age dependent form of epilepsy, of infancy and early childhood, that usually starts between 3 and 8 months of age. They were first diagnosed by a Dr West in 1841 who described them in his own son.

            The spasms are similar to the infant startle reaction, and involve brief, sudden contractions of muscle groups (usually neck, trunk and extremities). They are usually bilateral and symmetrical. If they are asymmetrical or focal, then this may suggest they are symptomatic. They are often described as head drops or jackknife movements, with the head dropping, arms can go up, and sometimes eyes rolling. Each one lasts less than a second, but they commonly occur in clusters lasting minutes. They tend to occur when very tired or soon after waking, and the child can cry before or soon after a spasm.

            They may be infrequent or atypical at onset, and are often misinterpreted with up to 88% of primary care physicians misdiagnosing them initially. They may initially diagnosed as colic, startle responses or normal infant behaviour. It is important to be suspicious of repetitive, stereotyped movements in infancy, and consider an EEG.

            They may also be called Salaam seizures or West Syndrome (which typically includes a typical EEG plus developmental delay plus clinical spasms).

            They can occur in children with existing developmental problems but they can also occur in developmentally normal children. Often development slows or regresses with continuing spasms.

            The reported incidence varies depending on what source you look up. It can vary from

               0.3 per 1000

               0.7 per 100 000

It is more common in males, and a family history exists in 3-6% of cases.

AETIOLOGY (CAUSES)

Lily is most likely Cryptogenic but with a slight possibility Symptomatic

            The causes can be divided into two main groupings:

1.      Cryptogenic/Idiopathic – no cause can be identified

- 10-15% of cases

- this group is getting smaller with time, as better tests become available that can detect smaller abnormalities.

- this group usually has normal development prior to the onset of IS

- there is  a 20% recurrence rate after anticonvulsant therapy

-30% can have other types of seizures or developmental delay

-70% have “complete” recovery

1.      Symptomatic – where a cause is identified

-divided into prenatal, perinatal and postnatal causes

- 85% have developmental delay

-15% have “complete” recovery

-65% have recurrence after anticonvulsant therapy

A table has been included listing possible causes. It is important to note that these causes are not extensively investigated for, as they don’t always change treatment or outcome. A list of usual investigations has been included below.

Other possible diagnoses that need to be excluded or considered:

Benign myoclonus of early infancy – normal EEG

Benign myoclonic epilepsy – good outcome, typical EEG

Early myoclonic encephalopathy (Aicardi)

Early infantile epileptic encephalopathy (Ohtahara) – can evolve into IS

Syndrome of periodic, lateralised spasms

Lennox Gastaut Syndrome

         The mechanism neurologically by which IS occurs is still unknown but there appear to be 4 main theories:

1.                  Disturbance of cortical synaptogenesis – a problem with modulating neurotransmitters at a specific period of brain development, the age corresponds to a critical period of maximal cerebral development.

2.                  Dysfunction of brainstem – biochemical or anatomic imbalance between neurons in gigantocellular area, may be related to altered brainstem serotonin metabolism

3.                  Abnormal cortical-subcortical interaction – cortical abnormality exerts noxious influence over brainstem, which then spreads to lenticular nuclei and to spinal cord

4.                  Abnormal brain-adrenal axis – Corticotrophin Releasing Hormone (causes release of ACTH) synthesis and activity is increased secondary to early stress during critical perinatal period, this is the least likely theory.

The true cause may be a combination of the above theories.

                                     INVESTIGATIONS

         Some of the investigations are routine screening tests for developmental delay, some are specific for IS.

EEG – this detects electrical activity of the brain, and involves putting electrodes on the scalp. It is painless, but the hair can get quite messy. The child needs to sit relatively still for about 20 minutes, often sleeping can give more information, and sometimes a 24 hour EEG is needed.

         The EEG shows hypsarrhythmia in 66% at onset, and it may be described as typical, evolving or modified, or otherwise. Currently, it is thought that even the nontypical hypsarrhythmia has the same clinical significance as true hypsarrhythmia. The report may describe high amplitude slow waves (1-7 Hz) chaotically mixed with sharp waves and spikes, and an interictal pattern showing hypsarrythmia and/or diffuse slow wave spikes at less than 3Hz and /or a burst suppression pattern ie an abnormal background. If there is some preservation of background it is called modified.

         Spasms may occur without an abnormal EEG however this pattern is usually present at some time during the course of the disorder, if only in slow wave sleep.

               So far all of Lily's MRI's have been normal

CT/MRI Scan – These are painless scans that show the anatomy of the brain. MRI is much more sensitive and picks up smaller lesions. 70% show some abnormality. The child needs to remain very still for this and therefore often requires a general anaesthetic. It is important to have this done if possible before ACTH is commenced, as ACTH can cause dilatation of ventricles and appearances suggestive of atrophy (thinning) of the brain.

Cerebrospinal Fluid (CSF) – This requires a lumbar puncture (needle into the back, to take some of this fluid which is around the spinal cord and the brain). It shows cells, protein, antibodies (in particular antibodies to herpes, cytomegalovirus and rubella), and is mostly used to detect infections. It is not always done.

Blood, Urine – These are usually used to detect inborn metabolic problems, infections (current and past), routine biochemical tests, and thyroid function. Also, chromosome studies can be done

Woods Light – This is a simple test with a UV light close to the skin, it helps to diagnose Tuberose Sclerosis.

If surgery is being considered, then SPECT (single photon emission cerebral tomography) or PET can be used (shows functional areas of the brain) in conjunction with the EEG and MRI to try to pinpoint localised lesions. It is not clear what the significance of focal lesions is, so these are not routinely done as they don’t change the prognosis or treatment in most cases.

         Also, a review by genetics specialists may be indicated when trying to determine if the cause is hereditary or familial. This can be important for families who want more children, to try and determine the risk for future pregnancies.

TREATMENT

The aim is to stop the spasms with minimal side effects, with no recurrence of seizures, and to try to get normal development back on track. IS is usually resistant to standard antiepileptic medications, but newer treatments have showed pretty good results. It is important to note that no large studies have been performed and therefore regimes are not standardised, and vary considerably worldwide.

Steroids – it is not known how they work. They can have serious side effects that need to be closely watched for.

1.                  ACTH – 60-80% respond, it is usually a short course of treatment. ACTH is a synthetic form of a natural substance made by the pituitary gland in the brain.

2.                  Prednisone – 50% respond (low dose), some studies have shown this to have a similar response to ACTH and some have shown ACTH to be better.

The optimal dose and duration of treatment are not widely agreed on:

                  Daily ACTH – 5-180IU/d

                  Hydrocortisone (oral) – 5-25 mg/kg/d

                  Prednisone – 2-10mg/kg/d

(I was unable to find any studies for hydrocortisone)

The questions of low versus high dose, and oral versus injectable steroids have still not been clearly answered.

         Steroids have a relatively high relapse rate, which usually occurs within 2-3 months of treatment. A second course of treatment can be used, and has been shown to be successful in up to 66%.

         The side effects are important to monitor for:

-          suppression of the immune system – need to limit exposure to infections

- high blood pressure, osteoporosis, kidney stones, fluid and electrolyte problems (salt, potassium), elevated blood sugar

- increased appetite, gastrointestinal upset, bleeding or diarrhoea

-  transient brain atrophy (thinning), apathy, hypotonia, irritability, intracranial bleeding

Also, they need to be tapered when ceasing to allow natural body steroid production to recover.

Vigabatrin – this is a newer drug and is an irreversible inhibitor of GABA transaminase. It is not currently approved by the FDA in the USA for treatment in children, but has been used worldwide for up to 10 years for the treatment of IS. The best results are in symptomatic cases but is still effective for cryptogenic cases. The dose ranges from 50-200 mg/kg/d divided over 2 doses. There is a relapse rate but this is mainly in the cryptogenic group. It is used both as a monotherapy and an add-on therapy.

           The side effects occur in about 25% and include hyperexcitability and hypotonia. It can also cause an increase in seizures. It does not change MRI appearances, does not require blood monitoring, and adult studies have shown no cognitive impairment. Children that respond have shown significant improvement in cognitive functions.

           Studies comparing vigabatrin versus ACTH as first line treatment (1997) have shown their efficacy to be similar in cryptogenic cases, although they are very small studies and only followed through for a short time:

-Vigabatrin – 50% responded (100-150 mg/kg/d) within 2 weeks, with progressive EEG improvement. 13% had side effects (often transient) which included drowsiness, hypotonia and irritability.

-ACTH – 75% responded but 20-30% relapsed within 3 months, only low doses were used, more effective in perinatal hypoxic injury. 37% had side effects which included drowsiness, hypotonia and irritability.

In this particular study, if one wasn’t effective, then swapping medication was effective in more than 50% of cases.

Surgery – it is still not clear what the role of surgery is. Control of spasms has occurred following surgery for structural abnormalities and in some cases with cortical hypometabolic lesions.

Ketogenic diet – see link

Pyridoxine (B6) – This is used in Japan in conjunction with valproate and has a lower success rate (around 40%). If low dose ACTH is added then this success rate doubles, but relapses are around 20%. This was the treatment regime commonly used, vigabatrin was not available.

Early Intervention – this is a vital part of treatment and requires assessment by a therapist (the earlier the better). It involves physiotherapy, occupational therapy and speech therapy. Most countries have this available. This gives the child the best chance for maximising development.

                                        PROGNOSIS

         This considers control of spasms, developmental progress and development of other seizures. The figures below are based on older studies, prior to the introduction of newer treatments.

         The prognosis is strongly influenced by structural abnormalities underlying.

-20-25% overall regain “normal” development (40%  if idiopathic)

 -30% + develop other types of seizures

-up to 20% may develop autism or hyperactivity disorders. This is closer to 10% if there isn’t a diagnosis of tuberose sclerosis

- 65% had spasms cease before the age of 2, if spasms persist then it is usual for them to be replaced by other types of seizures by 5 years old.

           The prognosis is better if there is a short time between onset of IS and onset of treatment, if the response to treatment is good, or if the development prior to the onset of spasms is normal.

           The pattern of the hypsarrhythmia does not correlate with outcome, and although the severity of the hypsarrhythmia may have clinical significance this is not commonly reported on.

                                             Other children

           The estimated risk is around 1.5% in other siblings, and 0,7% for first degree relatives. These figures may be higher when underlying causes are identified, particularly if these are familial or genetic.