Limbic encephalitis is a neurological syndrome characterized by inflammation of the brain with alterations in behavior and cognition, inflammation of the medial temporal lobes on brain imaging is most characteristic, but other brain regions may also be involved [1]. Most of the CNS autoantibodies can result in some form of limbic encephalitis [8]. Limbic encephalitis can be broadly categorized into two groups: the first group which is associated with antibodies against intracellular neuronal antigens (frequently associated with cancers and responds poorly to treatment), and the second group with antibodies directed against cell membrane or extracellular antigens (less frequently associated with cancers, and responds favorably to immunotherapy) [9, 10].

Limbic encephalitis is one of the neurological emergencies, and treatment needs to be commenced early to reduce long term morbidity and mortality [7]. However, full neuronal-specific antibody testing results can take several weeks, and testing for some of the newest antigens may not be available in most of the centres. As seen in this case, it is challenging for treating Neurologists to treat a critically ill patient for a prolonged period with incomplete information. The recent advance to the diagnostic criteria for possible autoimmune encephalitis and consensus on beginning empiric immunotherapy for autoimmune encephalitis [11] has facilitated early diagnosis and early immunotherapy in limbic encephalitis.

Another main challenge, in this case, is the initial antibodies testing and screening for malignancy (whole-body CT scan and tumor markers) were all negative. Nevertheless, the subacute clinical presentations of short-term memory decline, mood change, and seizures are in keeping with the diagnosis of limbic encephalitis. The intermittent episodes of speech difficulty could be due to seizure, or the Broca’s area involvement of the encephalitis. The fact that this patient responded well to the immunotherapy again supports the diagnosis of autoimmune or paraneoplastic limbic encephalitis. Abnormal PET scan and biopsy of the thymus have eventually confirmed the etiology of the limbic encephalitis.

A broad differential diagnosis and an extensive workup for autoimmune, paraneoplastic, and infective cause are crucial in patients with limbic encephalitis. The main differential diagnosis for limbic encephalitis is Herpes simplex encephalitis. Diagnosis of Herpes simplex encephalitis was ruled out by negative HSV-PCR in the CSF analysis in this case.

The diagnostic criteria of paraneoplastic limbic encephalitis proposed by Paraneoplastic Neurological Syndromes Euronetwork [12] include subacute onset of seizures, short-term memory loss, confusion and psychiatric symptoms; neuropathological or neuroradiological evidence of limbic system involvement; exclusion of other etiologies of limbic dysfunction; and demonstration of a cancer within 5 years of the diagnosis of the neurological disorder or demonstration of a well-characterized paraneoplastic antibody. Our patient fulfilled the Euronetwork diagnostic criteria for paraneoplastic limbic encephalitis.

The association between limbic encephalitis and Hodgkin’s lymphoma has been given the eponym of Ophelia syndrome [2], in memory of Shakespeare’s character in ‘The Tragedy of Hamlet, Prince of Denmark’. Ophelia syndrome is rare in patient with Hodgkin lymphoma. Although medial temporal lobes involvement is most characteristic in Ophelia syndrome, other brain regions may also be involved.

From our knowledge, unihemispheric cerebral involvement has not been reported among cases of PNS in Hodgkin lymphoma. Unihemispheric cerebral involvement can be seen in a rare chronic neurological disorder, called Rasmussen’s encephalitis. Rasmussen’s encephalitis is characterized by pharmaco-resistant epilepsy, and progressive neurological and cognitive deterioration due to unilateral inflammation of the cerebral cortex [13]. Although Rasmussen encephalitis is classically described as a childhood encephalopathy, the unusual adult-form variant has been described. The adult onset Rasmussen’s syndrome usually exhibit a slower course and a better outcome [13,14]. Nevertheless, this case is clinically not in keeping with Rasmussen’s syndrome.

About half of all autoimmune encephalitis cases are antibody-negative. The detection of auto-antibodies plays an important role in diagnosis and classification of the PNS syndrome. SOX1 antibody, PCA2 antibody, and metabotropic glutamate receptor-5 antibody (mGluR5 Abs) have reported in cases of Ophelia syndrome [15,16]. Knowledge about auto-antibody in Ophelia syndrome is still limited as Ophelia syndrome itself is a rare disorder. In this case, all the antibody tests were negative, including SOX1 antibody and PCA2 antibody. Tests for mGluR5 Abs is not available in the laboratory here.

We conclude that in all cases of limbic encephalitis, or whenever a paraneoplastic disorder is suspected, an extensive tumor workup (including a PET scan) should be initiated promptly. Although paraneoplastic neurological syndrome in Hodgkin lymphoma commonly affecting the mesial temporal regions (Ophelia syndrome), other brain regions may also be involved.