Acta Neurol Belg DOI 10.1007/s13760-015-0493-1
LETTER TO THE EDITOR
Anti-GAD antibodies, a rare cause of limbic encephalitis: a case report Yannick Van Ael1 • Rizvana Amir2 • Patrick Cras1
Received: 1 May 2015 / Accepted: 23 May 2015 Ó Belgian Neurological Society 2015
Keywords Anti-GAD antibodies Limbic encephalitis Nonparaneoplastic form Plasma exchange
Introduction Limbic encephalitis refers to an inflammatory process involving the hippocampal regions, amygdala and less frequently frontobasal and insular regions. Symptoms include changes in behavior and mood such as irritability and depression, sleep disturbances, seizures, and short-term memory deficits. Two forms do exist: paraneoplastic and nonparaneoplastic. We describe a patient with a nonparaneoplastic form of limbic encephalitis, associated with anti-GAD antibodies, with good response to plasma exchange.
& Yannick Van Ael [email protected] Rizvana Amir [email protected] Patrick Cras [email protected] 1
Department of Neurology, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, Edegem, Belgium
2
Department of Neurology, AZ Sint-Maarten Hospital, Leopoldstraat 2, 2800 Mechelen, Belgium
Case report A healthy 26-year-old woman, with a history of migraine, consulted in a peripheral hospital because of amnesia and confusion since 2 weeks. There was no fever. Upon admission, clinical neurological examination was unremarkable. Blood tests were normal. Brain MRI scan showed prolonged T2-time in the right hippocampal region with cortical diffusion restriction on DWI and without contrast enhancement. EEG was performed and showed no abnormalities. CSF analysis showed seven white blood cells per mm3 with slightly elevated protein level and seven isolated oligoclonal bands. Initially she was treated with levetiracetam, but because of episodic strange smells and frequent de´ja`-vu experiences after 1 week, carbamazepine was associated. She was transferred to our hospital because of clinical deterioration. Based upon clinical picture and MRI abnormalities (Fig. 1a), diagnosis of limbic encephalitis was made. Whole body PET-CT scan was performed and showed no signs of malignancy. Serum anti-YO, anti-Hu, anti-NMDA and anti-VGKC antibodies showed to be negative. Anti-GAD 65 antibody levels were highly elevated (performed by radioimmunoassay). Treatment with intravenous corticosteroids at immunosuppressive doses was started, without any clinical improvement after a few days. A switch to plasma exchange therapy resulted in a good clinical and radiological response (Fig. 1b) Clinical follow-up with periodic determining of anti-GAD 65 antibody levels after subsequent plasma exchange therapy showed a steady decline of symptoms, with reducing antiGAD 65 antibody levels (Fig. 2). In a period over almost 2 years one relapse was noticed with clinical and radiological repercussions. Patient suffered from partial epilepsy and short-term memory deficits. There was a
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Acta Neurol Belg
Discussion
Fig. 1 a Coronal and axial FLAIR MR showing abnormalities in right hippocampal region with cortical diffusion restriction (before plasma exchange). b Coronal and axial FLAIR MR showing resolution of right hippocampal lesion (2 months after start plasma exchange)
IU 9000 8000 7000 6000 5000 4000 3000 2000 1000 0
Fig. 2 Decline of anti-GAD 65 antibody levels over almost 2 years. October 2012 shows extinctive measurements during and after plasma exchange sessions. In January 2013, there is a clinical relapse with short-term memory deficits and partial epilepsy and slight increase of titers (black arrow), with need for new plasma exchange sessions
slight increase in titer of anti-GAD 65 antibodies. New plasma exchange therapy resulted in relief of signs. Further follow-up is ongoing.
123
Limbic encephalitis is characterized by three features: a core amnesic syndrome, complex-partial and secondarygeneralized seizures and affective disturbances [1]. It was first described by Brierley et al. and Corsellis et al. in the 1960s, as a clinicopathological entity with mediotemporal lobe symptoms caused by inflammatory lesions in limbic structures in adults [2]. It may occur as a paraneoplastic or nonparaneoplastic condition. In paraneoplastic form of limbic encephalitis, onconeural antibodies are directed against intracellular antigens. These include Hu, Ma2, collapsing response-mediator protein 5 (CRMP5) and amphiphysin. Patients with a nonparaneoplastic form of limbic encephalitis are associated with antibodies to neuronal cellsurface antigens; they generally have a better prognosis compared to patients with paraneoplastic forms. The most common antibodies in nonparaneoplastic forms of limbic encephalitis are antibodies directed against voltage-gated potassium channels (VGKC). Other antibodies directed to NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABABRs), and leucine-rich glioma inactivated 1 (LGI1) have also been identified by use of indirect immunohistochemistry on rodent brain sections [3]. Standardly these tests are being performed both in serum and cerebrospinal fluid, because of the higher sensitivity and specificity in the latter. Much more rare is limbic encephalitis associated with high levels of glutamic acid decarboxylase (GAD) antibodies. GAD catalyzes the synthesis of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. GAD antibodies are found at lower titers in insulin-dependent diabetes mellitus (IDDM). They are also associated with a number of neurological conditions, such as stiff-person syndrome, nystagmus and cerebellar syndromes [5]. Reports of patients with limbic encephalitis associated with GAD antibodies so far are scarce, a recent review [3] numbered 31 patients overall. It often concerns young adult women without tumors and temporal lobe epilepsy is usually dominating upon clinical presentation. Levels of GAD antibodies are usually higher than 1000 IU. Our patient showed levels above 7000 IU. Follow-up showed a slow decrease of these antibodies after initiation of plasma exchange therapy. Limbic encephalitis associated with GAD antibodies has a chronic course that finally stabilizes. Treatment consists of immunotherapies or plasma exchange. Seizure control in these patients is difficult, despite intense anticonvulsive treatment [4].
Acta Neurol Belg
Our patient showed a disappearance of the MRI lesions, as well as a good response on anticonvulsive treatment. Conflict of interest of interest.
The authors declare that there are no conflicts
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent required.
2. Honnorat J (2010) Autoimmune limbic encephalitis: an expanding concept. Lancet Neurol 9(1):24–25 3. Vincent A et al (2011) Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 10:759–772 4. Malter MP et al (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478 5. Finelli PF (2011) Autoimmune limbic encephalitis with GAD antibodies. Neurohospitalist 4:178–181
For this type of study formal consent is not
References 1. Samarasekera SR et al (2007) Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies. J Neurol Neurosurg Psychiatry 78:391–394
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LETTER TO THE EDITOR
Anti-GAD antibodies, a rare cause of limbic encephalitis: a case report Yannick Van Ael1 • Rizvana Amir2 • Patrick Cras1
Received: 1 May 2015 / Accepted: 23 May 2015 Ó Belgian Neurological Society 2015
Keywords Anti-GAD antibodies Limbic encephalitis Nonparaneoplastic form Plasma exchange
Introduction Limbic encephalitis refers to an inflammatory process involving the hippocampal regions, amygdala and less frequently frontobasal and insular regions. Symptoms include changes in behavior and mood such as irritability and depression, sleep disturbances, seizures, and short-term memory deficits. Two forms do exist: paraneoplastic and nonparaneoplastic. We describe a patient with a nonparaneoplastic form of limbic encephalitis, associated with anti-GAD antibodies, with good response to plasma exchange.
& Yannick Van Ael [email protected] Rizvana Amir [email protected] Patrick Cras [email protected] 1
Department of Neurology, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, Edegem, Belgium
2
Department of Neurology, AZ Sint-Maarten Hospital, Leopoldstraat 2, 2800 Mechelen, Belgium
Case report A healthy 26-year-old woman, with a history of migraine, consulted in a peripheral hospital because of amnesia and confusion since 2 weeks. There was no fever. Upon admission, clinical neurological examination was unremarkable. Blood tests were normal. Brain MRI scan showed prolonged T2-time in the right hippocampal region with cortical diffusion restriction on DWI and without contrast enhancement. EEG was performed and showed no abnormalities. CSF analysis showed seven white blood cells per mm3 with slightly elevated protein level and seven isolated oligoclonal bands. Initially she was treated with levetiracetam, but because of episodic strange smells and frequent de´ja`-vu experiences after 1 week, carbamazepine was associated. She was transferred to our hospital because of clinical deterioration. Based upon clinical picture and MRI abnormalities (Fig. 1a), diagnosis of limbic encephalitis was made. Whole body PET-CT scan was performed and showed no signs of malignancy. Serum anti-YO, anti-Hu, anti-NMDA and anti-VGKC antibodies showed to be negative. Anti-GAD 65 antibody levels were highly elevated (performed by radioimmunoassay). Treatment with intravenous corticosteroids at immunosuppressive doses was started, without any clinical improvement after a few days. A switch to plasma exchange therapy resulted in a good clinical and radiological response (Fig. 1b) Clinical follow-up with periodic determining of anti-GAD 65 antibody levels after subsequent plasma exchange therapy showed a steady decline of symptoms, with reducing antiGAD 65 antibody levels (Fig. 2). In a period over almost 2 years one relapse was noticed with clinical and radiological repercussions. Patient suffered from partial epilepsy and short-term memory deficits. There was a
123
Acta Neurol Belg
Discussion
Fig. 1 a Coronal and axial FLAIR MR showing abnormalities in right hippocampal region with cortical diffusion restriction (before plasma exchange). b Coronal and axial FLAIR MR showing resolution of right hippocampal lesion (2 months after start plasma exchange)
IU 9000 8000 7000 6000 5000 4000 3000 2000 1000 0
Fig. 2 Decline of anti-GAD 65 antibody levels over almost 2 years. October 2012 shows extinctive measurements during and after plasma exchange sessions. In January 2013, there is a clinical relapse with short-term memory deficits and partial epilepsy and slight increase of titers (black arrow), with need for new plasma exchange sessions
slight increase in titer of anti-GAD 65 antibodies. New plasma exchange therapy resulted in relief of signs. Further follow-up is ongoing.
123
Limbic encephalitis is characterized by three features: a core amnesic syndrome, complex-partial and secondarygeneralized seizures and affective disturbances [1]. It was first described by Brierley et al. and Corsellis et al. in the 1960s, as a clinicopathological entity with mediotemporal lobe symptoms caused by inflammatory lesions in limbic structures in adults [2]. It may occur as a paraneoplastic or nonparaneoplastic condition. In paraneoplastic form of limbic encephalitis, onconeural antibodies are directed against intracellular antigens. These include Hu, Ma2, collapsing response-mediator protein 5 (CRMP5) and amphiphysin. Patients with a nonparaneoplastic form of limbic encephalitis are associated with antibodies to neuronal cellsurface antigens; they generally have a better prognosis compared to patients with paraneoplastic forms. The most common antibodies in nonparaneoplastic forms of limbic encephalitis are antibodies directed against voltage-gated potassium channels (VGKC). Other antibodies directed to NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABABRs), and leucine-rich glioma inactivated 1 (LGI1) have also been identified by use of indirect immunohistochemistry on rodent brain sections [3]. Standardly these tests are being performed both in serum and cerebrospinal fluid, because of the higher sensitivity and specificity in the latter. Much more rare is limbic encephalitis associated with high levels of glutamic acid decarboxylase (GAD) antibodies. GAD catalyzes the synthesis of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. GAD antibodies are found at lower titers in insulin-dependent diabetes mellitus (IDDM). They are also associated with a number of neurological conditions, such as stiff-person syndrome, nystagmus and cerebellar syndromes [5]. Reports of patients with limbic encephalitis associated with GAD antibodies so far are scarce, a recent review [3] numbered 31 patients overall. It often concerns young adult women without tumors and temporal lobe epilepsy is usually dominating upon clinical presentation. Levels of GAD antibodies are usually higher than 1000 IU. Our patient showed levels above 7000 IU. Follow-up showed a slow decrease of these antibodies after initiation of plasma exchange therapy. Limbic encephalitis associated with GAD antibodies has a chronic course that finally stabilizes. Treatment consists of immunotherapies or plasma exchange. Seizure control in these patients is difficult, despite intense anticonvulsive treatment [4].
Acta Neurol Belg
Our patient showed a disappearance of the MRI lesions, as well as a good response on anticonvulsive treatment. Conflict of interest of interest.
The authors declare that there are no conflicts
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent required.
2. Honnorat J (2010) Autoimmune limbic encephalitis: an expanding concept. Lancet Neurol 9(1):24–25 3. Vincent A et al (2011) Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 10:759–772 4. Malter MP et al (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470–478 5. Finelli PF (2011) Autoimmune limbic encephalitis with GAD antibodies. Neurohospitalist 4:178–181
For this type of study formal consent is not
References 1. Samarasekera SR et al (2007) Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies. J Neurol Neurosurg Psychiatry 78:391–394
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