The paraneoplastic syndrome (PNS) associated with anti-Ma2 antibodies presents with limbic, diencephalic, and/or brainstem encephalitis.Reference Dalmau, Graus and Villarejo ¹ It is commonly reported in association with testicular germ cell tumors in young male patients, with non-small-cell lung cancer (SCLC) being the second most common associated tumor.Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² It has also been reported with breast, ovarian, parotid, colonic, esophageal, renal malignancies, melanoma, and non-Hodgkin’s lymphoma,Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² but never in association with Hodgkin’s lymphoma (HL). We report the first case associated with HL in a 60-year-old male presenting with neuropsychiatric symptoms, cataplexy, hypoglycemic episodes, and vertical supranuclear gaze palsy (VSGP).

A 60-year-old man with a 25-year history of well-controlled epilepsy developed subacute impairment in short-term memory and agitation that caused noncompliance with his anticonvulsants, resulting in an increase in his focal seizures, characterized by left- and occasionally right-side clonic movements preceded by alteration in speech and occasional postictal confusion. He developed new episodes of spontaneous sudden loss of tone, resulting in falls without loss of consciousness or difficulty speaking, suggestive of cataplexy. He also developed excessive daytime sleepiness (EDS) and unexplained hypoglycemic episodes, despite normal insulin, C-peptide, and a.m. cortisol. A year and a half later, he presented in the movement disorder clinic with difficulty reading due to an inability to look down. Family history was unavailable as he was adopted. Examination revealed reduced vertical gaze, which improved with oculocephalic maneuver, suggestive of VSGP. “Serpentine” saccades were observed on upgaze. There was mild upper limb ataxia, but no gait ataxia or parkinsonism (Video 1; see Supplementary Materials). His electroencephalogram showed asymmetrical bihemispheric frontotemporal slowing (left >right) without epileptiform discharges. A nonenhanced brain MRI showed mild generalized atrophy without any signal change or midbrain atrophy. Genetic testing for Niemann–Pick C (NPC) was negative. Serum lactate and muscle biopsy were normal. An abdominal CT done as part of a workup for his hypoglycemic episodes revealed a peripancreatic mass, subsequently diagnosed as HL (stage IA) on biopsy. A chest CT did not reveal any lung abnormality. He was treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy and 22 cycles of radiation therapy, which improved short-term memory, mood, cataplexy, and hypoglycemic episodes, but not VSGP. A follow-up CT of thorax, abdomen, and pelvis showed no evidence of metastasis. A normal whole-body FDG–PET scan excluded other active malignancies. A paraneoplastic screen, including anti-Hu, Yo, Ri, Ma2, CV2, and amphiphysin, returned positive for anti-Ma2 antibodies in the serum; confirmed by immunoblot. For his epilepsy with unremarkable neuroimaging, anti-thyroperoxidase (TPO) was ordered, and found to be markedly elevated (>3000; ref: <34 IU/ml) with normal serum T3, T4, and TSH. Because of the cooccurrence of two known autoantibodies, HLA typing was done, which showed the presence of A2, A11, B39, B51, DR11, DR16, DQ5, DQ7, DR51, and DR52. He was subsequently treated with intravenous immunoglobulin (IVIg) 2 g/kg divided over 3 days, followed by 1 g/kg per month for 6 months with prednisone 20 mg p.o. daily for 6 months, which he tolerated well despite no further improvement in his VSGP.

The clinical presentation of anti-Ma2 PNS results from isolated or combined limbic, diencephalic, and/or brainstem involvement in 90% of patients.Reference Dalmau, Graus and Villarejo ¹ While limbic involvement causes confusion, cognitive deterioration, and psychomotor seizures, brainstem dysfunction results in VSGP, diplopia, and dysarthria.Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² Diencephalic involvement leads to EDS, cataplexy, and hypnogogic hallucinations.Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² In 82% of patients, the PNS precedes tumor diagnosis by 2–36 months, while 18% develop PNS from 1 month to 14 years after tumor detection.Reference Hoffmann, Jarius and Pellkofer ² The subacute presentation with cataplexy, EDS, and VSGP preceding the diagnosis of HL and stabilization of the neurological syndrome after chemotherapy and radiation therapy for HL confirmed the association in our patient. His brain MRI was unremarkable, which can be seen in 18% of patients with anti-Ma2 encephalitis.Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² Cerebrospinal fluid examination was not done in our patient. Hypoglycemia has been reported with HL,Reference Kulkarni, Zlabek, Farnen and Capla ³ but never in association with anti-Ma2 encephalitis. HL is believed to produce a stimulating antibody to the insulin receptor, which has not yet been identified.Reference Kulkarni, Zlabek, Farnen and Capla ³

More than 90% of patients with brainstem involvement, especially those with additional limbic and diencephalic dysfunction, develop eye movement abnormalities, with VSGP seen in 60% of them.Reference Dalmau, Graus and Villarejo ¹ Due to the inability to generate a straight vertical saccade, our patient’s eyes moved in a “serpentine” manner, likely related to intact horizontal saccades, adding up to move the eyes vertically. A similar phenomenon has been described as a “round-the-houses” sign in early progressive supranuclear palsy (PSP), where the eyes move in a lateral arc while generating a vertical saccade.Reference Quinn ⁴ In our patient, there was no parkinsonism to suggest PSP, and genetic testing for the NPC that may present with VSGP, ataxia, and cognitive impairment was negative.Reference Salsano, Umeh, Rufa, Pareyson and Zee ⁵ Patients with anti-Ma2 brainstem encephalitis fare relatively better than others with paraneoplastic brainstem encephalitis, such as those associated with anti-Hu and anti-Ri autoantibodies.Reference Blaes ⁶ Improvement or stabilization of neurological features has been reported in 50–60% of patients with anti-Ma2 PNS after treatment of malignancy along with immunotherapy with steroid, IVIg, plasma exchange, or cyclophosphamide,Reference Dalmau, Graus and Villarejo ^{1 ,} Reference Hoffmann, Jarius and Pellkofer ² as was seen in our case. Although the paraneoplastic screen of our case did not include anti-Ma1 antibodies, it should be tested in patients with anti-Ma2 PNS, as its presence suggests a more likely association with nontesticular cancers and bears a worse prognosis.Reference Dalmau, Graus and Villarejo ¹

The presence of two clinically independent autoantibodies (anti-Ma2 and anti-TPO) in our patient along with a presumed third antibody causing hypoglycemic episodes suggests a likely predisposition to autoimmunity. Although specific PNS antibodies are associated with specific cancers,Reference Graus, Delattre and Antoine ⁷ no large studies have been conducted to identify HLA genotypes in patients with specific cancers developing PNS versus those who do not. A single study found a significantly higher frequency of HLA-DQ2 and HLA-DR3 in patients with SCLC and anti-Hu PNS (n=53), compared with healthy controls (n=2440).Reference de Graaf, de Beukelaar and Haasnoot ⁸ There was a trend toward a higher frequency of HLA-DQ2 in those with SCLC and anti-Hu versus those with SCLC alone (n=24), but this was not statistically significant, likely related to the small size of the SCLC group.Reference de Graaf, de Beukelaar and Haasnoot ⁸ No similar HLA studies have been performed in anti-Ma2 PNS patients. Interestingly, association with specific HLA alleles have been reported in patients with autoimmune encephalitis linked to IgLON5Reference Sabater, Gaig and Gelpi ⁹ and LGI1Reference Kim, Lee and Moon ^{10 ,} Reference van Sonderen, Roelen and Stoop ¹¹ antibodies, independent of malignancy. Larger studies involving patients with autoimmune encephalitis, with and without malignancies, may provide a link to screen for these disorders, leading to early diagnosis and improved clinical outcomes.

We report the first anti-Ma2 PNS case associated with HL and describe serpentine saccades. The presence of at least two separate autoantibodies in our patient (anti-Ma2 and anti-TPO) and probably a stimulating antibody to the insulin receptor associated with HL supports the need for further investigation into HLA genotypes and their relationship to the development of autoantibody-mediated PNS. Our patient’s HLA genotypes may form the precedence for future HLA studies in similar cases.