Limbic encephalitis

Limbic encephalitis
The limbic system within the brain.
Classification and external resources
Specialty
ICD-10	G04.81
ICD-9-CM	323.81
DiseasesDB	30707
Patient UK	Limbic encephalitis
MeSH	D020363

Limbic encephalitis is a form of encephalitis, a disease characterised by inflammation of the brain. Limbic encephalitis is caused by autoimmunity: an abnormal state where the body produces antibodies against itself. Some cases are associated with cancer and some are not. Although the disease is known as "limbic" encephalitis, it is seldom limited to the limbic system and post-mortem studies usually show involvement of other parts of the brain. The disease was first described by Brierley and others in 1960 as a series of three cases. The link to cancer was first noted in 1968 and confirmed by later investigators.

The majority of cases of limbic encephalitis are associated with a tumour (diagnosed or undiagnosed). In cases caused by tumour, cure is only achieved when the tumour is removed completely (this is not always possible). Limbic encephalitis is classified according to the auto-antibody that causes the disease.

The most common types are:

• Anti-Hu, which is associated with small-cell carcinoma of the lungs.
• Anti-Ma2, associated with germ-cell tumours of the testis.
• Anti-NMDAR, associated with tumors of the ovaries, commonly teratomas.

Since 2002 following a report of case of a 21-year-old woman subacutely developed memory loss subsequent to gastroenteritis similar cases of non paraneoplastic LE its association with auto-antibody and response to steroid has been described. Limbic encephalitis associated with voltage‐gated potassium channel antibodies (VGKC‐Abs) may frequently be non‐paraneoplastic. A recent study of 15 cases of limbic encephalitis found raised VGKC‐Abs associated with non‐paraneoplastic disorders and remission following immunosuppressive treatment.

History

Clinical Features	Pathology	Year	Syndromes
Subacute onset of episodic memory impairment, disorientation and agitation, commonly associated with seizures, hallucinations, sleep disturbance	Medial temporal lobe inflammation	1960	Subacute encephalitis of later adult life mainly affecting the limbic areas
		1968	Limbic Encephalitis association with Carcinoma
		2008	Paraneoplastic LE with Lung Carcinoma, thymoma,
		2002	Non Paraneoplastic LE

Paraneoplastic Limbic Encephalitis (PNLE)

Symptoms and signs

Symptoms develop over days or weeks. The subacute development of short-term memory deficits is considered the hallmark of this disease, but this symptom is often overlooked, because it is overshadowed by other more obvious symptoms such as headache, irritability, sleep disturbance, delusions, hallucinations, agitation, seizures and psychosis, or because the other symptoms mean the patient has to be sedated, and it is not possible to test memory in a sedated patient.

Investigation

Cerebrospinal fluid (CSF)

Examination of cerebrospinal fluid (CSF) shows elevated numbers of lymphocytes (but usually < 100 cells/µl); elevated CSF protein (but usually <1.5 g/l), normal glucose, elevated IgG index and oligoclonal bands. Patients with antibodies to voltage-gated potassium channels may have a completely normal CSF examination.

Neuroimaging

MRI brain is the mainstay of initial investigation pointing to limbic lobe patholoy revealeing increased T2 signal involving one or both temporal lobes in most cases.

Serial MRI in LE starts as an acute disease with uni- or bilateral swollen temporomesial structures that are hyperintense on fluid attenuation inversion recovery and T2-weighted sequences. Swelling and hyperintensity may persist over months to years, but in most cases progressive temporomesial atrophy develops.

PET CT scan: Not an essential investigation but can help in suspected cases with MRI negative for early diagnosis.

Neuro-electrophysiology

EEG: Mostly nonspecific slowing and epileptiform activity arising from temporal lobes.

Diagnosis

The diagnosis of limbic encephalitis is extremely difficult and it is usual for the diagnosis to be delayed for weeks. The key diagnostic test (detection of specific auto-antibodies in cerebrospinal fluid) is not routinely offered by most immunology laboratories. Some of the rarer auto-antibodies (e.g., NMDAR) have no commercially available assay and can only be measured by a very small number of research laboratories worldwide, further delaying diagnosis by weeks or months. Most patients with limbic encephalitis are initially diagnosed with herpes simplex encephalitis, because the two syndromes cannot be distinguished clinically. HHV-6 (human herpes virus 6) encephalitis is also clinically indistinguishable from limbic encephalitis.

There are two sets of diagnostic criteria used. The oldest are those proposed by Gultekin et al. in 2000.

Gultekin criteria
EITHER, Pathological demonstration of limbic encephalitis
OR, All four of: Short-term memory loss, seizures, or psychiatric symptoms suggestive of limbic system involvement <4 years between onset of neurological symptoms and cancer diagnosis Exclusion of metastases, infection, metabolic and nutritional deficits, stroke and side-effects of therapy that may cause limbic encephalopathy At least one of CSF with inflammatory findings Hyperintensity of the temporal lobes bilaterally on MRI FLAIR or T2 EEG with epilepsy or slow activity involving the temporal lobes focally

A revised set of criteria were proposed by Graus and Saiz in 2005.

Graus and Saiz criteria

All four of Subacute onset (<12 weeks) of seizures, short-term memory loss, confusion, and psychiatric symptoms Neuropathologic or radiologic evidence (MRI, SPECT, PET) of involvement of the limbic system Exclusion of other possible aetiologies of limbic dysfunction Demonstration of a cancer within 5 years of the diagnosis of neurologic symptoms, or the development of classic symptoms of limbic dysfunction in association with a well-characterized paraneoplastic antibody (Hu, Ma2, CV2, amphiphysin, Ri)

The main distinction between the two sets of criteria is whether or not the detection of a paraneoplastic antibody is needed for diagnosis.

Antibodies against intracellular neuronal antigens

The main antibodies within this group are those against Hu, Ma2, CV2, amphiphysin and Ri. The syndrome of anti-Ma2 encephalitis may be clinically mistaken for Whipple's disease.

Antibodies against cell membrane antigens

The main antibodies within this group are those against anti-N-methyl-D-aspartate receptors (NMDAR) and the voltage-gated potassium channel-complex (VGKC-complex). Anti-NMDAR encephalitis is strongly associated with benign tumours of the ovary (usually teratomas or dermoid cysts). Anti-VGKC-complex encephalitis is most often not associated with tumours.

Patients with NMDAR encephalitis are frequently young women who present with fever, headache and fatigue. This is often misdiagnosed as influenza, but progresses to severe behavioural and personality disturbance, delusions, paranoia and hallucinations. Patients may therefore initially be admitted to a psychiatric ward for acute psychosis or schizophrenia. The disease then progresses to catatonia, seizures and loss of consciousness. The next stage is hypoventilation (inadequate breathing) requiring intubation, orofacial dyskinesia and autonomic instability (dramatic fluctuations in blood pressure, temperature and heart rate).

Treatment

Limbic encephalitis is a rare condition with no randomised-controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide and rituximab.

If an associated tumour is found, then recovery is not possible until the tumour is removed. Unfortunately, this is not always possible, especially if the tumour is malignant and advanced.

External links

• PNSEURONET: the PNSEURONET group provides information on paraneoplastic neurological syndromes for medical specialists worldwide.
• "Diagnosis: 'Forgetting Everything'", New York Times, November 11, 2007.