Limbic encephalitis

Clinical features


Limbic encephalitis presents with a diversity of symptoms including confusion, depression, agitation, anxiety, memory deficits, and dementia. The typical clinical picture is characterized by the subacute onset of confusion with marked reduction of short-term memory. Seizures are not uncommon and they may antedate by months the onset of cognitive deficits. Other patients have a more insidious onset with depression or hallucinations which can confuse the diagnosis with that of a psychiatric illness. According to a recent large series of 50 patients, diagnostic criteria for paraneoplastic limbic encephalitis should includes:

 

    Typical clinical symptoms.
    Click to enlarge Figure 1. Brain MRI and PET showing the typical involvement of hippocampus in limbic encephalitis.

     

    • Less than four years to tumor diagnosis

     

    • Pathological or radiological involvement (MRI, SPECT or PET) of the limbic system (Figure 1)
    • Exclusion of other diagnoses.

Of the 50 patients, 83% had a subacute progressive course. Symptoms were short term memory loss (in 84% of patients), epileptic seizures (50%), acute confusional syndrome (46%), further psychiatric symptoms (personality change, hallucinations, depression, in 42%), brainstem symptoms (26%), signs of hypothalamic involvement (22%), cognition disturbance (14%), and signs of involvement of other neurological systems in 42%. In 50% of patients the tumor was a small cell lung carcinoma, 20% had a testicular tumor, and 8% had breast cancer.

 Associated antibodies

Anti-Hu antibodies are present in up to 50% of patients with limbic encephalitis and lung cancer. The other half is seronegative. Therefore the absence of onconeural antibodies does not rule out the diagnosis. A minority of patients with limbic encephalitis and lung cancer may harbour anti-CV2 (CRMP5) or amphiphysin antibodies. Recently, low titers of anti-voltage-gated potassium channel (VGKC) antibodies have been reported in a few patients with this syndrome and no onconeural antibodies.


Anti-Ma2(Ta) antibodies are present in the great majority of patients with limbic encephalitis and testicular cancer. Unlike patients with lung cancer, these patients in addition of limbic encephalitis usually present with diencephalic and upper brainstem symptoms that identify a characteristic syndrome (figure 2).

Click to enlarge

 

Figure 2. Clinical spectrum of patients with anti-Ma2 antibodies.
 

 

Treatment

As in many paraneoplastic neurological syndromes of the central nervous system, limbic encephalitis rarely improves with treatment. The best chance to reverse the syndrome is to induce a complete response of the tumor. Immunotherapy probably is effective is some patients and a trial with intravenous immunoglobulins, steroids or plasmapheresis is indicated. Patients with anti-Ma2 antibodies or without onconeural antibodies are more likely to improve than those with anti-Hu antibodies.

 Selected references


1. Alamowitch S, Graus F, Uchuya M, Reñé R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain 1997; 120: 923-8.

2. Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481-94.

3. Pozo-Rosich P, Clover L, Saiz A, et al. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol 2003;54:530-3.

4. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001;50:339-48.

5. Voltz R, Gultekin SH, Rosenfeld MR et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 1999:340:1788-95.