Neuroradiology (2011) 53:837851 DOI 10.

1007/s00234-010-0832-0

CONTINUING EDUCATION

Autoimmune-mediated encephalitis
Philippe Demaerel & Wim Van Dessel & Wim Van Paesschen & Rik Vandenberghe & Koen Van Laere & Jennifer Linn

Received: 23 November 2010 / Accepted: 24 December 2010 / Published online: 27 January 2011 # Springer-Verlag 2011

Abstract Autoimmune-mediated encephalitis may occur as a paraneoplastic or as a non-paraneoplastic condition. The role of neuroimaging in autoimmune-mediated encephalitis has changed in the last decade partly due to improvements in sequence optimisation and higher field strength and partly due to the discovery of an increasing number of antibodies to neuronal cell and cell membrane antigens. Imaging is important since it can support the clinical diagnosis particularly in the absence of antibodies. Structural imaging findings can be subtle and are usually best seen on FLAIR images. A progressive as well as a relapsingremitting course can be observed. Autoimmunemediated encephalitis is classically linked to involvement of the hippocampus and amygdala, but extensive changes in the temporal cortex, basal ganglia, hypothalamus, brain stem, frontal and parietal cortex are not unusual. This report is based on a review of the literature (except the literature in
P. Demaerel (*) : W. Van Dessel Department of Radiology, University Hospitals K.U.Leuven, Herestraat 49, 3000 Leuven, Belgium e-mail: philippe.demaerel@uzleuven.be W. Van Paesschen : R. Vandenberghe Department of Neurology, University Hospitals K.U.Leuven, Herestraat 49, 3000 Leuven, Belgium K. Van Laere Department of Nuclear Medicine, University Hospitals K.U.Leuven, Herestraat 49, 3000 Leuven, Belgium J. Linn Department of Neuroradiology, University Hospital Mnchen, Munich, Germany

Japanese) and own findings in patients with autoimmunemediated encephalitis. Keywords Limbic . Paraneoplastic . Autoantibody . MR imaging . Autoimmune

Background Autoimmune-mediated encephalitis (AME) may occur as a paraneoplastic or non-paraneoplastic condition and remains, despite continuous advances in diagnosis and treatment, incompletely understood. Limbic encephalitis (LE) is probably the best known AME, but other entities that will be briefly included in this review are paraneoplastic cerebellar degeneration and opsoclonus-myoclonus syndrome. The term LE was introduced in 1968 in association with cancer but can occur in the absence of malignancy too [1]. LE is a T-cell immune-mediated subacute neurological disorder with antibodies against an intracellular or membrane-bound antigen. Recently, a classification has been proposed for AME on the basis of the location of the antigen [2, 3]. AME better describes these neuroimmunological diseases than LE, although the latter term is still widely used. It is beyond the scope of this report to list all antibody (Ab)-related disorders but only those with frequently associated imaging findings. The commonly reported antigens inside the neuron include Hu, CV2, amphiphysin, Ri, Yo and Ma2 and are often referred to as onconeural antigens. The neoplasms associated with these antigens are small cell lung cancer (SCLC), testicular tumours, ovarian teratoma and breast cancer, but the presence of these antigens is not necessarily linked to a paraneoplastic encephalitis. Antibodies to Ma2

838

Neuroradiology (2011) 53:837851

are mainly associated with testicular tumours and it is not uncommon to find only a microscopic intratubular germ cell tumour without evidence of cancer in these patients [4]. Antibodies to glutamic acid decarboxylase (GAD) have been reported in stiff-person syndrome (characterized by symmetrical muscle rigidity and stiffness) in a nonparaneoplastic setting, often in association with other autoimmune disorders, such as insulin-dependent diabetes mellitus [57]. This syndrome has also been reported in association with thymoma and renal cell carcinoma [8, 9]. Antigens in the cell membrane (neuropil antobodies) include voltage-gated potassium channels (VGKC), and N-methyl-Daspartate (NMDA), AMPA, -aminobutyric acid (GABA) and glycine receptors and can be associated with a neoplasm (e.g. thymoma, SCLC, prostate adenocarcinoma) but are often non-paraneoplastic. VGKC-Ab have been demonstrated in acquired neuromyotonia and related disorders involving the peripheral nervous system as well as in Morvans syndrome (neuromyotonia and autonomic disorders) [10]. A separate group concerns patients with an ovarian teratoma and antigens that co-localize with EFA6A, a hippocampal protein upregulated by NMDA receptors and involved in the regulation of dendritic development of hippocampal neurons [11]. Ances et al. have reported five patients with until now unidentified neuropil Ab, different from the VGKC [12]. The corresponding cell membrane antigen co-localize with synaptophysin and spinophilin and are more concentrated in the hippocampus and cerebellum, but individual characterization has not yet been achieved. Antibodies against the metabotropic glutamate receptor type 1 (mGLuR1) have been reported in patients with cerebellar ataxia and Hodgkins lymphoma [13]. Antineuronal nuclear antibody type 2 (anti-Ri) has been decribed in opsoclonus-myoclonus syndrome and breast carcinoma, but can occasionally be observed in association with other cancers [14]. Paraneoplastic cerebellar degeneration (PCD) has been linked to nine different antibodies to neuronal antigens including Yo, Ri, Ma, Hu and mGluR1 [15]. Ovarian, lung and breast cancer and Hodgkins lymphoma have been reported to be more often associated with PCD. Rasmussen encephalitis is a T-cell-mediated inflammatory disorder involving one cerebral hemisphere and resulting in frequent intractable seizures. Autoimmune antibodies may play a role in the pathogenesis, but there is not sufficient evidence to confirm this [16]. Rasmussen encephalitis will not be discussed here.

Fig. 1 Coronal FLAIR image at 3 T shows subtle lesion in the left amygdala in a patient with anti-GAD and anti-GABA antibodies

impairment, e.g. amnestic syndrome [1719]. It has been suggested that the most common etiology of de novo temporal lobe epilepsy in adults is LE. Patients with CV2 antibodies can have chorea. Mesodiencephalic encephalitis can be seen in patients with Ma2 antibodies. The antibodies that target neuronal antigens are thought to cause the neurological symptoms. The clinical features together with signs of brain inflammation (mild cerebrospinal fluid (CSF) pleocytosis and CSF oligoclonal bands) justify the diagnosis of nonparaneoplastic AME confirmed by follow-up and absence of evidence of cancer. Adults with opsoclonus-myoclonus syndrome and an underlying malignancy present with ataxia, horizontal gaze paresis and often laryngospasm and jaw dystonia [14]. The definite diagnosis of paraneoplastic LE requires the clinical presentation and morphological evidence of involvement of the limbic system and the presence of antibodies or a

Diagnosis The clinical presentation of AME may include partial seizures, mood and behavioural changes and cognitive
Fig. 2 Bilateral involvement of the hippocampus and amygdala is seen in a patient with paraneoplastic encephalitis and a colon adenocarcinoma

Neuroradiology (2011) 53:837851

839

Fig. 3 Progressive bilateral (right more than left) hippocampal atrophy over a time span of 15 months in a patient with autoantibody-mediated encephalitis without detectable antibodies (ac)

Fig. 4 Demonstration of extralimbic lesions in nonparaneoplastic encephalitis (a) and in anti-GAD antibody encephalitis with subsequent detection of a thymoma (b)

Fig. 5 Axial FLAIR (a) and gadolinium-enhanced T1weighted (b) images in a nonparaneoplastic encephalitis without detectable antibodies, showing the irregular enhancing lesions in the hippocampus and anterior temporal lobe

840

Neuroradiology (2011) 53:837851

tumour within 5 years after the onset of the symptoms (http://www.pnseuronet.org) [20]. Patients with PCD often present with ataxia, diplopia, nystagmus and vertigo. In up to 50% of the patients with clinical evidence of LE, no antibodies can be identified [21]. On the other hand, antibodies can be found in the absence of imaging and clinical signs of LE too. In 60% of the patients, antibodies are detected prior to the detection of cancer.

The specificity for the presence of a tumour is almost 100% but the sensitivity is only 60% [22]. The search for antibodies is important and many of the appropriate antibody tests are commercially available today. Neuropathology shows a mononuclear inflammatory cell infiltration, loss of neurons and proliferation of astrocytes. This appearance does not allow a neuropathological confirmation of the paraneoplastic etiology.

Fig. 6 Anti-VGKC antibody non-paraneoplastic encephalitis with normal MR imaging (a) but FDG-PET showed intense hypometabolism covering temporoparietooccipital lobes bilaterally without evidence for focal hypermetabolism (b, c)

Neuroradiology (2011) 53:837851

841

Fig. 7 Paraneoplastic cerebellar degeneration with anti-Purkinje cell antibodies in a patient with B-cell non-Hodgkins lymphoma. PET/CT demonstrated several enlarged para-aortic and retro-esophagal lymph nodes and the supraclavicular lymph node was biopsied

Table 1 Predilection sites of involvement in autoimmune-mediated encephalitis Literature findings AME with neuronal antigen (often paraneoplastic) GAD: hippocampus, amygdala, cerebral cortex (can be thymoma related) Ma2: hippocampus, amygdala, hypothalamus, thalamus, midbrain CV2: Purkinje cell: Ri: VGKC: hippocampus, amygdala, basal ganglia NMDA: hippocampus, cerebral cortex Authors own experience GAD: hippocampus, cerebral cortex (can be thymoma related) Ma2: hippocampus and anterior temporal cortex, hypothalamus, mammillary bodies (testicular cancer) CV2: hippocampus, amygdala, basal ganglia, insular cortex (lung cancer) Purkinje cell: cerebellum (B-cell lymphoma related) Ri: brain stem (breast cancer related) VGKC: hippocampus, amygdala and anterior temporal cortex NMDA: hippocampus, cerebral cortex, basal ganglia, thalamus Paraneoplastic: hippocampus and parahippocampal area (colon, prostate, testicular cancer) Non-paraneoplastic: hippocampus, amygdala, thalamus, anterior temporal cortex

AME with cell membrane antigen (often non-paraneoplastic)

AME without detectable antibodies

842

Neuroradiology (2011) 53:837851

Fig. 8 Axial FLAIR images in anti-GAD antibody encephalitis with subsequent detection of a thymoma show bilateral cortical lesions in the frontal, parietal and temporal lobes (ac)

Fig. 9 Anti-Ma2 antibody encephalitis in a patient with testicular cancer and behavioural disturbances and amnesia. Axial FLAIR images show bilateral involvement of the amygdala and hippocampus as well as pathological changes in the hypothalamus and optic chiasm (a, b). Follow-up imaging 8 months later show progressive swelling of

the amygdalohippocampal region and extension into the adjacent anterior temporal cortex on the right side (ce). Coronal T2-weighted images 14 months (f) and 2 years (g) later show progressive hippocampal atrophy

Neuroradiology (2011) 53:837851

843

Imaging Introduction and general findings MR imaging is the modality of choice for demonstrating the pathological changes associated with AME. It is accepted that

approximately 70% of patients who have LE get abnormalities in the temporal lobes [23]. However, imaging can remain normal in a subset of cases and changes can be extremely subtle particularly at the early stage of the disease (Fig. 1). AME typically involves the hippocampus and amygdala on one or both sides and then corresponds to LE (Fig. 2).

Fig. 10 Anti-CV2 antibody encephalitis in a patient with a neuroendocrine tumour. Axial FLAIR images (ad) show involvement of the left amygdala, hippocampus, the anterior temporal cortex and white matter and the right lentiform and caudate nucleus

844

Neuroradiology (2011) 53:837851

At presentation, a swelling of these structures is best seen on FLAIR images and is associated with a variable degree of increased signal [24]. In case reports, diffusion-weighted imaging has shown high signal within the affected areas, with or without decreased apparent diffusion coefficient [25, 26]. Follow-up will often show atrophy of the affected area (Fig. 3). Extralimbic paraneoplastic brain lesions are increasingly being reported [18] (Fig. 4). Both focal and meningeal contrast enhancement have been reported but are very unusual [11, 22, 27, 28] (Fig. 5). In general, it is not possible to differentiate paraneoplastic from non-paraneoplastic AME. Functional imaging is extremely helpful and more often demonstrates bilateral abnormalities that are complementary to structural imaging findings [29] (Fig. 6). Even in the absence of structural MRI abnormalities, fluorodeoxyglucose positron emission tomography (FDG-PET) may show hypermetabolism in the medial temporal lobe [12, 3032]. PET proved to offer additional information compared with MRI and may have potential for clinical course prediction and treatment follow-up [12]. In paraneoplastic cerebellar degeneration, cerebellar hypometabolism is more often seen than structural MRI changes [33]. Whole-body FDG-PET also plays a clear role for tumour detection for patients with paraneoplastic antibodies and no evidence of a tumour on structural imaging [34]. Ideally, whole-body FDG-PET/CT is recommended and can replace the combined chest and abdominal CT (Fig. 7) [35, 36]. We reviewed 19 patients, 14 presented with antibodies and 5 without antibodies. Seizures were the most common clinical presentation, followed by behavioural and mood changes. In nine patients, a tumour was found. Brain imaging findings were normal in two patients: one patient with Hodgkins lymphoma, anti-MGluR1 antibodies and a PCD and one patient with anti-GABA and anti-GAD antibodies in a non-paraneoplastic setting. Eleven patients had involvement of the amygdalohippocampal region, four presented with initial bilateral lesions and four with unilateral hippocampal abnormalities, and in three patients, there was progression from a unilateral to a bilateral involvement. Diffusion-weighted MRI was available in all patients and showed restricted diffusion in two cases. The initial extent of involvement did not influence outcome. Progressive atrophy occurred in most cases on follow-up. The imaging findings are summarized in Table 1 and are discussed in detail below. Imaging in AME with antigens inside the neuron Antibodies against GAD have been associated with paraneoplastic and non-paraneoplastic limbic encephalitis [6,

Fig. 11 Paraneoplastic cerebellar degeneration with anti-Purkinje cell antibodies in a patient with B-cell non-Hodgkins lymphoma. The first examination was obtained because of dizziness and unsteady gait and showed subtle lesions in the cerebellum on both sides (a). Follow-up 1 month later shows progression of the lesion in the left hemisphere (b) and progressive atrophy after 2 months (c)

Neuroradiology (2011) 53:837851

845

37]. Bilateral involvement of the amygdala and hippocampus has been described as well as extratemporal cortical lesions. Vernino and Lennon have reported 12 patients with thymoma-related encephalopathy, 9 of whom had limbic abnormalities and 3 had extralimbic cortical lesions [8]. VGKC and GAD were amongst the detected antibodies. We have seen one patient with anti-GAD antibody positive encephalitis who presented with several cortical lesions and in whom a thymoma was found (Fig. 8). Following the resection of the thymoma, the patient recovered completely. In one patient with anti-GAD and GABA antibodies, imaging showed subtle involvement of the hippocampal region, and in another one, imaging was normal. In antiMa2 encephalitis, MRI changes can be seen in the

amygdalohippocampal region but are frequently located in the hypothalamus, thalamus and midbrain. Contrast enhancement has been reported [38]. In two patients with anti-Ma2 antibodies, we found bilateral hippocampal lesions in both with extension in the anterior temporal cortex and with abnormalities in the hypothalamus and mammillary bodies in one (Fig. 9) [4]. The patient with anti-CV2 antibodies had initially relapsingremitting lesions in the caudate and lentiform nucleus and later involvement of the amygdala and hippocampus with extension in the insular cortex (Fig. 10). There was bilateral but asymmetrical involvement of the hippocampus with extension into the parahippocampal area in the two other patients with AME and a tumour but without detectable antibodies.

Fig. 12 Anti-Ri antibody encephalitis in a patient with a history of breast carcinoma and spastic tetraparesis and sensorimotor polyneuropathy. Axial T2 (a, b) and FLAIR (c, d) images show the diffuse involvement of the medulla oblongata and pons

846

Neuroradiology (2011) 53:837851

Paraneoplastic cerebellar degeneration has been associated with at least nine antineuronal antibodies. In a large series of 50 patients with PCD, there was no evidence of intracranial lesions in the acute stage [15]. There have been reports of cerebellar atrophy after several months. We observed cerebellar lesions in one patient with anti-Purkinje cell antibodies and a B-cell lymphoma (Fig. 11). Two patients with anti-Ri antibodies had involvement of the brain stem (Figs. 12 and 13). In a series of eight patients with opsoclonus-myoclonus syndrome and cancer who underwent brain MR imaging,

MRI was normal in five cases, temporal lobe lesions shown in two patients and dorsal brain stem lesions in one patient [14]. We found focal lesions in the dorsal brain stem in our patient (Fig. 13). Imaging in AME with antigens in the cell membrane (neuropil antobodies) AME due to VGKC-Ab is usually non-paraneoplastic. In 3 series of 27 patients, bilateral medial temporal lobe involvement was seen in 18 (66%) patients and unilateral involvement in 7 patients [7, 10, 39]. Imaging was normal in two patients. Involvement of the basal ganglia has been reported. We found extension of the unilateral MR changes beyond the hippocampus involving the amygdala and anterior temporal cortex in two patients with VGKC antibodies (Fig. 14). MR imaging was normal in the third patient but FDG-PET of the brain showed extended and intense hypometabolism covering temporoparietooccipital lobes bilaterally without evidence for focal hypermetabolism. Extralimbic frontal involvement has been reported in NMDA Ab-related encephalopathy [40], but MR imaging often remains normal too. Our patient with anti-NMDA had extensive lesions in the basal ganglia, thalamus, hippocampus and cortex (Fig. 15). In the remaining three patients, no Ab were found. Bilateral asymmetrical hippocampal involvement was seen in one patient, unilateral hippocampal involvement in another patient and left amygdalohippocampal involvement with extension in the anterior temporal cortex and thalamus in the third patient (Fig. 16). The patients with ovarian teratoma and antibodies to antigens that co-localize with EFA6A were characterized by the absence of limbic abnormalities in more than 60% of the patients and medial temporal lobe lesions were absent. Instead, a wide variation of cerebral and cerebellar cortical lesions is seen as well as brain stem involvement. Normal imaging findings have been reported too.

Differential diagnosis Hashimoto encephalopathy has to be considered as a differential diagnosis. It is found in patients with autoimmune thyroiditis which is associated with high levels of anti-thyroid antibodies in serum and CSF. Non-specific MR changes such as atrophy and white matter lesion occur in 50% of the patients. They often present with symptoms similar to those in (non)paraneoplastic encephalitis. Hashimoto encephalopathy can be seen in association with Sjgrens syndrome and systemic lupus erythematosus. A common feature of these diseases is the steroid responsiveness, but involvement of the limbic system on MR imaging

Fig. 13 Anti-Ri antibody encephalitis in opsoclonus-myoclonus without detectable neoplasm. Axial FLAIR (a, b) images show involvement of the midbrain and medulla oblongata on the right side

Neuroradiology (2011) 53:837851

847

is lacking. Steroid responsive LE has been reported and anti-white matter antibodies were detected [41]. Wernicke Korsakoff encephalopathy, Herpes simplex meningoencephalitis and gliomatosis cerebri or low grade glioma are to be considered amongst the differential diagnoses because of predominant involvement of the temporal lobe and/or thalamus. In the rare case with contrast enhancement, malignant tumours should be included in the differential diagnosis. Acute non-herpetic LE has been reported in Japan. In these cases, bilateral swelling of the medial temporal lobe was seen on MRI. The neurological signs and laboratory findings were similar to paraneoplastic LE but there is no evidence of a tumour [42]. Postictal changes after prolonged seizures can also result in MR changes involving the medial temporal lobe. Clinically, it can be difficult to distinguish metabolic encephalopathy, Alzheimer s disease or primary psychiatric disorders from (non)paraneoplastic encephalitis.

Occasionally, the imaging findings may resemble posterior reversible encephalopathy syndrome, an expression of neurotoxicity through a T-cell immunemediated response.

Treatment and prognosis In paraneoplastic neurological disorders, the search for a tumour and tumour treatment are mandatory and can result in a rapid improvement of the neurological signs and symptoms. Plasma exchange and long-term immunomodulation with intravenous immunoglobulins, in combination with high dose intravenous corticosteroids, are the classical treatments of AME. Generally speaking, therapy response is better in patients with antineural antibodies against cell membrane antigens, e.g. in

Fig. 14 Anti-VGKC antibody non-paraneoplastic encephalitis with unilateral involvement of the amygdala, hippocampus and adjacent anterior medial temporal cortex on the left side (ad). Note the swelling of the amygdala and hippocampus on initial presentation

with limited increase of signal intensity (a). FDG-PET at the same time showed hypermetabolism in the left anterior temporal lobe (e). Ictal perfusion imaging with 99mTc-ECD SPECT, co-registered with MR images, clearly showed an ictal onset zone at this region (f)

848

Neuroradiology (2011) 53:837851

Fig. 14 (continued)

patients withVGKC antibodies an improvement can be observed with immune therapy in 50 70% of the patients. Good therapeutic response has been reported in patients with a history of a treated adenocarcinoma and paraneoplastic encephalitis with anti-Hu antibodies several years later [24].

Conclusion AME is a complex immune-mediated disorder. Our insight in its pathogenesis is improving, and although it is a rare disorder, the disease is probably under-recognized. A wide range of structural and functional imaging findings is being

Neuroradiology (2011) 53:837851

849

Fig. 15 Anti-NMDA antibody non-paraneoplastic encephalitis with extralimbic lesions in the caudate nucleus, the lentiform nucleus and thalamus (a, b). Not the evidence of diffusion restriction on the apparent diffusion coefficient map (c) Fig. 16 Limbic encephalitis without antibodies and without detectable neoplasm. Involvement of the hippocampus, amygdala and adjacent anterior temporal cortex is visible on the initial examination (a, b). On the follow-up scan 1 month later, the bilateral lesions are better seen (c). Follow-up 2 weeks later shows further extension of the lesions in the temporal lobe on the left side and a periventricular lesion (d, e)

850

Neuroradiology (2011) 53:837851 10. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S (2004) Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62:11771182 11. Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J (2005) Paraneoplastic encephalitis, psychiatric symptoms and ovarian teratoma. Ann Neurol 58:594604 12. Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, Galetta SL, Dichter M, Alavi A, Rosenfeld MR, Dalmau J (2005) Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128:17641777 13. Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, Henzen-Logmans S, Vecht C, De Zeeuw C, Sekiyama N, Nakanishi S, Shigemoto R (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342:2127 14. Pittock SJ, Parisi JE, McKeon A, Roemer SF, Lucchinetti CF, Tan KM, Keegan BM, Hunter SF, Duncan PR, Baehring JM, Matsumoto JY, Lennon VA (2010) Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri). Arch Neurol 67:11091115 15. Shamsili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, Vecht C, Sillevis Smitt P (2003) Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126:14091418 16. Watson R, Jiang Y, Bermudez I (2004) Absence of antibodies to glutamata receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 63:4350 17. Anderson NE, Barber PA (2008) Limbic encephalitisa review. J Clin Neurosci 15:961971 18. Foster AR, Caplan JP (2009) Paraneoplastic limbic encephalitis. Psychosomatics 50:108113 19. Kayser MS, Kohler CG, Dalmau J (2010) Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry 167:1039 1050 20. Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, Hart IK, Honnorat P, Sillevis Smitt PAE, Verschuuren JJGM, Voltz R, Paraneoplastic Neurological Syndrome Euronetwork (2008) Management of paraneoplastic neurological syndromes: report of an EFNS Task Force Europa. Eur J Neurol 13:682690 21. Graus F, Delattre JY, Antoine JC, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler Ch, Verschuuren JJ, Vincent A, Voltz R (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75:11351140 22. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J (2000) Paraneoplastic limbic encephalitis: neurological symprtoms, immunological findings and tumour association in 50 patients. Brain 123:14811494 23. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S (2003) Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 78:13631368 24. Urbach H, Soeder BM, Jeub M, Klockgether T, Meyer B, Bien CG (2006) Serial MRI of limbic encephalitis. Neuroradiology 48:380386 25. Thuerl C, Mller K, Laubenberger J, Volk B, Langer M (2003) MR imaging of autopsy-proved paraneoplastic limbic encephalitis in non-Hodgkin lymphoma. Am J Neuroradiol 24:507511 26. Sener RN (2002) MRI and diffusion MRI in nonparaneoplastic limbic encephalitis. Comput Med Imaging Graph 26:339342 27. Launay M, Bozzolo E, Venissac N, Delmont E, Fredenrich A, Thomas P (2008) Paraneoplastic limbic encephalitis with positive anti-Ri antibodies and mediastinal seminoma. Rev Neurol 164:612619

reported. Temporal lobe changes are common but often extension beyond the amygdala and hippocampus is seen, involving extralimbic structures. MR imaging plays an important role in the diagnosis because of the non-specific clinical presentation.
Summary Paraneoplastic encephalitis often precedes the clinical manifestations of cancer with a delay of several months. Both limbic and/or extralimbic lesions can be observed in paraneoplastic encephalitis and in non-paraneoplastic (limbic) encephalitis. The imaging findings can be subtle and are usually better seen on (coronal) FLAIR images. A progressive as well as a relapsingremitting course can be seen. MRI can play an important role in reaching the correct diagnosis in patients without Ab, which can be of importance in the rapid initiation of a treatment. Structural and functional imaging play an important role in the screening for associated tumours.

Conflict of interest We declare that we have no conflict of interest.

References
1. Corsellis JA, Goldberg GJ, Norton AR (1968) Limbic encephalitis and its association with carcinoma. Brain 91:481496 2. Graus F, Saiz A, Dalmau J (2010) Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257:509517 3. Dalmau J, Bataller L (2006) Clinical and immunological diversity of limbic encephalitis: a model for paraneoplastic neurologic disorders. Hematol Oncol Clin North Am 20:13191335 4. Mathew RM, Vandenberghe R, Garcia-Merino A, Yamamoto T, Landolfi JC, Rosenfeld MR, Rossi JE, Thiessen B, Dropcho EJ, Dalmau J (2007) Orchiectomy for suspected tumor in patients with anti-Ma2-associated encephalitis. Neurology 20:900905 5. Bien CG, Urbach H, Schramm J, Soeder BM, Becker AJ, Voltz R, Vincent A, Elger CE (2007) Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 69:12361244 6. Mata S, Muscas GC, Naldi I, Rosati E, Paladini S, Cruciatti B, Bisulli F, Paganini M, Mazzi G, Sorbi S, Tinuper P (2008) Non-paraneoplastic limbic encephalitis associated with antiglutamic acid decarboxylase antibodies. J Neuroimmunol 199:155159 7. Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470478 8. Vernino S, Lennon VA (2004) Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 10:72707275 9. McHugh JC, Murray B, Renganathan R, Connolly S, Lynch T (2007) GAD antibody positive paraneoplastic stiff person synsdrome in a patient with renal cell carcinoma. Mov Disord 22:13431346

Neuroradiology (2011) 53:837851 28. McKeon A, Ahlskog E, Britton JA, Lennon VA, Pittock SJ (2009) Reversible extralimbic paraneoplastic encephalopathies with large abnormalities on magnetic resonance images. Arch Neurol 66:268271 29. Fauser S, Talazko J, Wagner K, Ziyeh S, Jarius S, Vincent A, Schulze-Bonhage A (2005) FDG-PET and MRI in potassium channel antibody-associated non-paraneoplastic limbic encephalitis with clinical course and neuropsychology. Acta Neurol Scand 111:338343 30. Basu S, Alavi A (2008) Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates. Mol Imaging Biol 10:131137 31. Scheid R, Lincke T, Voltz R, von Cramon DY, Sabri O (2004) Serial 18F-fluoro-2-deoxy-D-glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis. Arch Neurol 61:17851789 32. Provenzale JM, Barboriak DP, Coleman RE (1998) Limbic encephalitis: comparison of FDG-PET and MRI findings. Am J Roentgenol 18:16591660 33. Rubello D, Vitaliani R, Rigoni MT, Rampin L, Giometto B, Casara D, Zonzin GC, Zavagno G, Capirci C, Shapiro B, Muzzio PC (2005) A rare case of paraneoplastic cerebellar degeneration discovered by whole body F-18 FDG PET. Clin Nucl Med 30:704706 34. Younes-Mhenni S, Janier MF, Cinotti L, Antoine JC, Tronc F, Cottin V, Ternamian PJ, Trouillas P, Honnorat J (2004) FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 127:23312338

851 35. Bien CG, Elger CE (2007) Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav 10:529538 36. Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Grisold W, Honnorat J, Sillevis Smitt PA, Tanasescu R, Vedeler CA, Voltz R, Verschuuren JJ (2011) Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 18(1):19-e3. doi:10.1111/j.1468-1331.2010.03220.x 37. Cianci V, Labate A, Lanza P, Vincent A, Gambardella A, Branca D, Arcudi L, Aguglia U (2010) Non-paraneoplastic limbic encephalitis characterized by mesio-temporal seizures and extratemporal lesions: a case report. Seizure 19:446449 38. Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J (2001) Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 50:339348 39. Vincent A, Buckley C, Schott JM, Baker I, Dewar B-K, Detert N, Clover L, Parkinson A, Bien CG, Omer S, Lang B, Rossor MN, Palace J (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127:701712 40. Dalmau J, Tzn E, Wu HY (2007) Paraneoplastic anti-N-methylD-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:2536 41. Watanabe Y, Shimizu Y, Ooi S, Tanaka K, Inuzuka T, Nakashima K (2003) Steroid-responsive limbic encephalitis. Intern Med 42:428432 42. Asaoka K, Shoji H, Nishizaka S, Ayabe M, Abe T, Ohori N, Ichiyama T, Eizura Y (2004) Non-herpetic acute limbic encephalitis: cerebrospinal fluid cytokines and magnetic resonance imaging findings. Intern Med 43:4248