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This paper was prepared by Dr Clive Hawkins Consultant Neurologist / Senior Lecturer Royal Infirmary, Stoke on Trent and reviewed by Dr Sarosh Irani, John Radcliffe Hospital, Oxford

Acute disseminated encephalomyelitis (ADEM) accounts for up to one third of all known cases of encephalitis. This illness usually follows in the wake of exanthema or after other viral infections or immunisations. There is usually a latent period of days to two to three weeks. This illness was first described 250 years ago by the distinguished English physician, Clifton who noted that it occurred occasionally in patients who had smallpox. The white matter of the brain is predominantly affected and under the microscope it can be seen that there is invasion around small veins by white blood cells from the blood. Where these cells accumulate myelin is destroyed. The illness has been poorly understood and a variety of terminologies used to describe it, these including post infectious, parainfectious or post vaccinial.

Clinical Presentation

The clinical presentation of ADEM despite different causes is similar. The illness usually begins with non specific symptoms such as fever, headache, stiff neck, vomiting and anorexia. These are rapidly followed by depression of consciousness in which the patient may become confused, stuporous, delirious and occasionally entering into coma. During this early period neurological examination usually shows focal neurological signs such as bilateral optic neuritis, ataxia of the limbs, clumsiness in walking, paralysis down one side and seizures may occur. The duration of these symptoms is variable, some cases lasting a few weeks to a month, and other fatal cases having a rapid progressive course over a number of days. The clinical sign that correlates most closely with the prognosis is the level of consciousness. The illness usually has monophasic course i.e. once it is over, further attacks rarely develop. Recently long term studies of patients with ADEM have shown that a small number later on develop multiple sclerosis.

Investigations

The cerebrospinal fluid is frequently abnormal showing an increase in white cells and protein. The electroencephalogram is abnormal in most cases showing diffuse slowing. Magnetic resonance imaging typically shows multiple areas of abnormality in the white matter of the brain.

Differential Diagnosis

The differential diagnoses of ADEM include acute meningitis, acute viral encephalitis and acute multiple sclerosis. Differentiation of these diseases is not easy, certainly in the early stages. In viral encephalitis the CSF is often abnormal and a rise in specific viral antibody may occur. To distinguish ADEM from multiple sclerosis in the initial phases may be more difficult. Magnetic resonance imaging and CSF examination may help.

Pathology

The brain at post mortem may appear entirely normal or may show the signs of congestion. Histologically the basic lesions consist of infiltrations of mononuclear cells from the blood which occur around small veins in the white matter. Demyelination occurs and is limited to the area of the perivenous cellular cuff. These are different from the lesions found in multiple sclerosis.

Evidence for an Immunological aetiology

There is general agreement that a causative organism cannot be isolated from the central nervous system of patients with ADEM. The association of the disease with an antecedent infection or immunisation suggests an immunological process and detailed laboratory studies involving measurement of anti-brain antibodies and of cellular immune responses to specific myelin antigens have shown that these patients indeed have mounted an allergic response against their own brain constituents.

Treatment

The ideal form of treatment is immunomodulation to be instituted without delay once the diagnosis is made. High doses of steroids can often lead to a very rapid resolution of symptoms with an excellent prognosis. Overall the prognosis is good where the diagnosis is made early and the appropriate therapy instituted without delay.

Medical text was created in 2010 by Dr Baba Aji, Specialist Registrar to Professor Tom Solomon, Consultant Neurologist, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK.

Hashimoto's Encephalopathy, Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), non - vasculitic autoimmune meningoencephalitis.

Background

Hashimoto's encephalitis (inflammation / swelling of the brain) was first described in 1966. It is a rare, probably autoimmune condition. ( a disorder in which the immune system mistakenly attacks and destroys healthy body tissues). It is usually associated with high levels of thyroid antibodies in the blood. Hashimoto's encephalitis has been reported in children, adults and the elderly all over the world. It is more common in females than males.

What are the symptoms?

The clinical presentation is often a depression of brain function, drowsiness and sometimes coma. Two types have been described: (1) The relapsing and remitting type (symptoms at times worse and other times better) which manifests with encephalopathy and stroke – like episodes. (2) The diffuse progressive (widely dispersed) type which has a slow onset, progressive course with occasional fluctuations and manifest with psychiatric symptoms such as confusion, disorientation and psychosis. Either of these may present with tremors, jerks or epileptic seizures.

What are the causes?

Currently, the exact cause is unknown. The thyroid antibodies are a marker rather than the cause of the problem. Thyroid function is usually normal.

How is it diagnosed?

It is a diagnosis of exclusion and the differential is wide, ranging from stroke-like episodes, Alzheimer's disease, Creutzfeldt-Jacob disease, to rare inborn errors of metabolism. Useful tests include Magnetic Resonance Imaging (MRI) of the brain, Electroencephalogram (EEG), Cerebrospinal Fluid (CSF) findings, endocrine and metabolic screens, and viral studies.

How is it treated?

Most patients with Hashimoto's encephalitis improve with high dose steroids (Prednisolone). However, improvement may take weeks or even months. Because of the improvement with steroids, some experts refer to the condition as "steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT)". Plasma exchange and intravenous immunoglobulin (IVIG) have been used in some patients. The prognosis with treatment is generally good. Steroids are often continued for many months.

A useful reference is

www.ncbi.nlm.nih.gov

1: Neurology. 1991 Feb;41(2 ( Pt 1)):228-33. Related Articles, Links
Hashimoto's encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers--report of 5 cases.

Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE.

Department of Neurology, University of Newcastle upon Tyne, UK.

We describe 5 patients with a relapsing encephalopathy in association with Hashimoto's disease and high titers of anti-thyroid antibodies. The presentation is usually with a subacute onset of confusion, alteration in conscious level, and focal or generalized seizures. The relapsing course, association with myoclonus or tremulousness, and episodes of stroke-like deterioration are characteristic features. The long-term prognosis is favorable with steroid therapy, though additional immunosuppressive therapy may be required. Neurologic investigation typically shows a diffusely abnormal EEG, high CSF protein level without pleocytosis, and normal brain CT and cerebral angiogram. Isotope brain scan may show patchy abnormal uptake. Hashimoto's encephalopathy should be recognized as a definite neurologic entity and added to the list of CNS complications of thyroid disease.

Publication Types:
Case Reports
Review
Review of Reported Cases

PMID: 1992366 [PubMed - indexed for MEDLINE]

This paper was prepared by Dr Ian Hart Senior Lecturer in Neurology Neuroimmunology Group, University Department of Neurological Science Clinical Sciences Building, Walton Centre, Lower Lane Liverpool

Introduction

Rasmussen's encephalitis (RE; also called Rasmussen's syndrome) is a progressive inflammation of the part of the brain called the cerebral cortex, which is made up of a right and a left hemisphere. The disease starts at one site in one hemisphere and spreads to adjoining areas on the same side. Curiously, it does not spread to the other hemisphere. The inflammation leads to loss of nerve cells and scar formation and usually results in severe disability. Although RE is most often diagnosed in children under the age of 10 years, it can also start in adolescence and adulthood. It is a rare disorder and probably affects one person in every 500 000 to 1 000 000.

Clinical features

The clinical problems in RE are determined by which areas of the affected hemisphere are inflamed: each area has different functions. As the disease spreads, more areas are damaged and the greater the severity and range of the disabilities. Typically, the disease progresses relentlessly until most of one hemisphere is affected. The inflammation burns out by itself only rarely before severe disability has occurred. However, the speed of the spread varies between patients. At one end of the spectrum, the disease advances rapidly over a few weeks or months. At the other end, progression occurs slowly over several years. This slower clinical variant seems to be more common in adolescents and adults than in children. It is possible that there are milder forms of RE that we fail to recognize.

The typical clinical features are:

Epilepsy

Usually, the first sign of the disease is focal epilepsy. If the motor cortex (the area that controls movement) is affected, the patients have motor seizures with jerking of one side of the body. Sometimes the motor seizures become continuous, and this state is called continuous partial epilepsy. Similarly, if the temporal cortex is affected, patients have temporal lobe seizures (complex partial seizures) with altered awareness of their surroundings.

Although the seizures start at one site, they can spread to the rest of the brain and cause generalized epilepsy with loss of consciousness. As the disease progresses, the seizures become more frequent, more severe, and more difficult to treat with standard anti-epileptic drugs.

Neurological deficits

There is convincing evidence that in most patients RE is an autoimmune disorder. Many patients have antibodies in their blood that bind to nerve cells and which are capable of damaging the brain. Of particular interest is an antibody that binds to an important nerve protein called the type-3 glutamate receptor (GluR3). In addition, activated immune cells called T cells that are toxic to nerve cells are found in inflammatory brain tissue in biopsies from RE patients.

In most patients, it is not clear what triggers the abnormal immune response, although sometimes RE has followed an otherwise minor bacterial or viral infection, or head injury.

Diagnosis

A serious disease needs intensive investigation. The tests are designed to confirm RE and to exclude other conditions. Diseases that can mimic RE include viral and toxoplasma encephalitis, autoimmune disorders such as vasculitis, and tumours. The most useful investigations are

• Brain scans. MR, SPECT, and if available PET scans are useful. Figure 1 shows an MR brain scan of severe RE.
• Blood tests. These include assays for a range of antibodies and tests to exclude infection.
• Lumbar puncture. Spinal fluid is examined for evidence of inflammation and infection.
• Brain biopsy. This is needed to confirm the diagnosis.
• Electroencephalogram (EEG). This records the electrical activity of the brain and is useful in characterising the type of seizures the patient has.

Treatment

Because in RE the seizures often do not improve with anti-epilepsy drugs and the disease only ends with destruction of the affected cerebral hemisphere, surgical removal of large areas, sometimes all, of the hemisphere became a standard treatment. However, the research evidence of autoimmune abnormalities in many patients, and the clear need for effective medical therapy early in the disease to prevent progression, helped prompt trials of immune therapy.

Immune therapy

Trials of various combinations of powerful drugs that suppress the immune system (prednisolone, azathioprine, methotrexate, and cyclophosphamide) and therapies that modulate the function of the immune system (plasma exchange and intravenous immunoglobulin) have been tried. However, these trials have usually been performed in individual patients and there are no good data on the optimum combination, dosing, or duration of immune treatments.

It seems likely that to modify or arrest the progression of a chronic, destructive disease such as RE, most patients will need a combination of therapies at high dose for prolonged periods – perhaps indefinitely.

The combination of daily oral prednisolone (a steroid) and monthly pulses of intravenous immunoglobulin appears promising. All eight patients, mostly with adult-onset RE, that we have treated in this way for up to five years have had useful improvement in their epilepsy control and, so far, have not developed any new disabilities. Sometimes, the disabilities that were present before treatment have improved.

Regardless of the type of immune therapy used, the outcome is likely to be better the earlier the treatment is started. The decision to start immune therapy is not taken lightly. These treatments have many potentially serious side effects, especially in children, and require very careful monitoring.

Surgery

This is the traditional treatment for advanced RE, and is used mainly to improve seizure control in patients with established disability. The extent of the surgery is determined by the severity, duration, rate of progression, and site of the disease, and the age of the patient. In patients with severe disease, all of the affected hemisphere may be removed (hemispherectomy).

When we find out more about the best use of immune therapy in RE, it is hoped that fewer patients will need surgery.

Anti-epileptic drugs

As epilepsy in RE is usually difficult to control, patients often try many drugs before the best combination is found. These drugs have no effect on progression of the underlying encephalitis.

Other therapies

Various anti-viral drugs have been tried in some patients thought to have RE. However, they are likely to be useful only when the patient has a viral encephalitis rather than autoimmune RE.

This paper was written by Dr Sarosh Irani and Professor Angela Vincent from the Department of Clinical Neurology, University of Oxford.

The major role of our immune system is to recognize and clear infection. Sometimes, however the components of the immune system – antibodies and white blood cells - may react with our own body to cause autoimmune diseases. When this reaction is against the brain, an autoimmune encephalitis is produced. Many cases of autoimmune encephalitis have recently been reported with antibodies against the N-methyl D-aspartate receptor (NMDAR). NMDARs help modulate the excitability of nerves and therefore antibodies against these receptors are likely to have an important role in directly causing the disease.

The clinical features of NMDAR-antibody associated encephalitis are distinctive and are prompting many clinicians to request the NMDAR-antibody test to diagnose this condition. The disease predominantly affects young patients, with around 30% of cases under 18 years of age. Females are affected more commonly than males

Once a patient has been diagnosed with NMDAR-antibody encephalitis, an underlying tumour should be excluded. While very few males have tumours detected (typically

At onset, the most distinctive features include prominent psychiatric symptoms with seizures, confusion and memory loss. Patients will sometimes show bizarre and often rather disturbing behaviours. Typically 10 to 20 days later, patients often develop a movement disorder, fluctuations in blood pressure, heart rate and temperature and may have a reduction in their level of consciousness. The movement disorder often consists of continuous writhing and twitching of face and limbs but can also be a generalised slowing-down of movements.

If this clinical pattern is recognized, other causes excluded (particularly infections) and the antibody result is positive, treatments should be started. Treatments consist of immune therapies (such as steroids, immunoglobulins and plasma exchange) and removal of a tumour, if present. Prompt therapies offer a good chance of substantial recovery in the majority of patients. However, such recovery is usually slow and many patients who return to work only do so after a year or two.

In summary, NMDAR-antibody encephalitis is a newly-described antibody-mediated disease that causes psychiatric features, confusion, memory loss and seizures followed by a movement disorder, loss of consciousness and autonomic fluctuations. The disease can respond well albeit often slowly to various immunotherapies and removal of an underlying tumour.