Paraneoplastic Progressive Downbeat Nystagmus, Ataxia and Sensorineural Hearing Loss due to the ANTI-Kelch-11 Protein Antibody

A 45-year-old man with a history of testicular seminoma treated 8 years earlier presented with chronic progressive truncal and limb ataxia, progressive sensorineural hearing loss, and episodic vertigo. Eye movement and neuro-otology examinations showed localizing abnormalities to the bilateral cerebellar flocculus, vermis, and bilateral cerebellar hemispheres. Audiometric testing showed bilateral symmetric sensorineural hearing loss. There was a normal MRI of the brain. Cerebrospinal fluid (CSF) showed modest lymphocytic pleocytosis, and there was an elevated serum choriogonadotrophic hormone. An abdominal CT scan showed a solitary, large retroperitoneal lymph node, and histopathologic examination of the node biopsy showed granulomatous inflammation without microorganisms; eventually, immunohistochemical markers confirmed the diagnosis of metastatic seminoma. Although normal neuroimaging and inflammatory CSF reaction suggested a paraneoplastic etiology, the initial paraneoplastic antibody testing was negative. Subsequent investigation identified a positive kelch-11 protein antibody, thus confirming the paraneoplastic connection between the metastatic seminoma and the subacute neurologic-cochleovestibular syndrome.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Paraneoplastic Progressive Downbeat Nystagmus, Ataxia and Sensorineural Hearing Loss due to the ANTIKelch-11 Protein Antibody Jorge C. Kattah, MD, Scott D. Eggers, MD, Sarah E. Bach, MD, Divyanshu Dubey, MD, Andrew B. McKeon, MD Abstract: A 45-year-old man with a history of testicular seminoma treated 8 years earlier presented with chronic progressive truncal and limb ataxia, progressive sensorineural hearing loss, and episodic vertigo. Eye movement and neuro-otology examinations showed localizing abnormalities to the bilateral cerebellar flocculus, vermis, and bilateral cerebellar hemispheres. Audiometric testing showed bilateral symmetric sensorineural hearing loss. There was a normal MRI of the brain. Cerebrospinal fluid (CSF) showed modest lymphocytic pleocytosis, and there was an elevated serum choriogonadotrophic hormone. An abdominal CT scan showed a solitary, large retroperitoneal lymph node, and histopathologic examination of the node biopsy showed granulomatous inflammation without microorganisms; eventually, immunohistochemical markers confirmed the diagnosis of metastatic seminoma. Although normal neuroimaging and inflammatory CSF reaction suggested a paraneoplastic etiology, the initial paraneoplastic antibody testing was negative. Subsequent investigation identified a positive kelch-11 protein antibody, thus confirming the paraneoplastic connection between the metastatic seminoma and the subacute neurologic– cochleovestibular syndrome. Journal of Neuro-Ophthalmology 2021;41:261–265 doi: 10.1097/WNO.0000000000001194 © 2021 by North American Neuro-Ophthalmology Society Department of Neurology (JCK, SB), Illinois Neurologic Institute, Peoria, Illinois; Department of Neurology (JCK, SB), Saint Francis Medical Center and University of Illinois College of Medicine; Department of Neurosurgery (JCK, SB), University of Illinois College of Medicine, Peoria, Illinois; Department of Pathology (JCK, SB), Neuropathology Section, University of Illinois College of Medicine, Peoria; Departments of Neurology (SDE, DD, AM) and Laboratory Medicine and Pathology (DD, AM), Mayo Clinic, Rochester, Minnesota. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Jorge C. Kattah, MD, Department of Neurology, Saint Francis Medical Center. 530 North GlenOak Avenue, Room 4646, Peoria, IL; E-mail: [e-mail] Kattah et al: J Neuro-Ophthalmol 2021; 41: 261-265 Drs. Kattah, Eggers, Dubey, and McKeon A 45-year-old man developed progressive gait difficulty over a 2-year period. In addition, he was experiencing spontaneous episodes of disabling vertigo, nausea, and vomiting. Episodes occurred approximately twice monthly and were of several hours duration. He lost the ability to play his guitar and developed dysarthria, progressive postural instability, and gait difficulty. A neurosurgical evaluation at another institution led to a C5-6 anterior cervical discectomy without improvement. He also noted simultaneous, progressive bilateral hearing loss. During the ensuing months, he became wheelchair bound because of truncal ataxia. He had a negative family history of ataxia, migraine, or hearing loss. He had undergone a left orchiectomy 8 years before a testicular seminoma, which was considered to be in remission. He had no history of nutritional deficiency or toxic exposure and was never exposed to ototoxic medications. Examination showed a normal mental status. He stood for seconds with a wide base but could not walk due to truncal ataxia. He had 4-limb dysmetria, action tremor, and dysdiadochokinesia (See Supplemental Digital Content, Video 1, http://links.lww.com/WNO/A452 second section). In addition, he had dysarthria without palatal tremor. The afferent visual examination, including visual acuities, was normal. slit lamp, and dilated fundus examinations showed normal structures. Ophthalmoscopy did reveal subtle low-amplitude primary position downbeat nystagmus (DBN; average slow phase velocity 4 deg/sec; Fig. 1, See Supplemental Digital Content, Video 1, http://links.lww.com/WNO/A452). In extreme lateral gaze, there was a coarse horizontal/DBN, with occasional brief rebound nystagmus on return to primary gaze. Vestibular testing showed normal bithermal caloric testing. However, he had decreased gain and phase lag with sinusoidal, lowfrequency oscillation, and short time constant with impulse rotation. The video head impulse showed decreased left 261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Video–oculography recording of visual fixation on a center target located straight ahead. Note DBN mixed with a horizontal left beat nystagmus. In lateral gaze (not shown), the nystagmus increased in intensity and amplitude, and the horizontal component was right beat in right gaze and left beat in left gaze. anterior canal gain of 0.55 (normal 0.7–1.0) and normal gain for the other canals, without corrective saccades. Combined visual/vestibular ocular response (VVOR) was normal. These combined findings indicated a partial, symmetric bilateral vestibulopathy, in addition to spontaneous DBN. The saccade main sequence showed right adduction saccade slowing compatible with a subclinical internuclear ophthalmoplegia (INO). Horizontal and vertical pursuit gains were bilaterally decreased. Fixation suppression of vestibular nystagmus was impaired. Positional testing was normal and did not increase DBN intensity. The recordings showing DBN, decreased pursuit gain, and impaired VOR suppression suggested bilateral functional impairment of the cerebellar flocculus (1,2). Truncal and limb dysmetria suggested functional impairment of the cerebellar hemispheres and anterior vermis. In addition, pure tone audiometry showed bilateral sensorineural hearing loss (Fig. 2). Laboratory testing showed normal routine blood count, sedimentation rate, liver and renal functions, and folate and vitamin B12 levels, and negative serum HIV and syphilis serologies. Additional ancillary testing included a normal right testicular ultrasound. Contrast enhanced CT scan of the abdomen showed 2 adjacent periaortic retroperitoneal adenopathies, located just below the left renal artery, the largest one measured 3.0 · 1.8 cm, and the smaller was 2.0 · 2.2 cm. A precontrast and post–contrast-enhanced brain MRI was normal without evidence of leptomeningeal enhancement. Given isolated adenopathy without associated visceral or peritoneal abnormalities, and with normal chest imaging, the radiologist recommended a biopsy. fratentorial superficial siderosis. A parenchymal neoplasm was effectively excluded with normal MRI; however, autoimmune, mitochondrial, toxic, and nutritional disorders remained as potential causes. In addition, in this age group, granulomatous and viral infections and postviral syndromes, demyelinating, or autoimmune etiologies were prime considerations. The preceding history of testicular seminoma raised the question of metastatic seminoma, and this possibility was further supported by the enlarged retroperitoneal node. Although leptomeningeal spread of a seminoma is unlikely, a paraneoplastic syndrome could be responsible for the clinical presentation. The radiologic differential suggested metastatic disease, lymphoma, and noncalcified granulomatous inflammation (Fig. 2). Lumbar puncture was therefore pursued. Cerebrospinal fluid (CSF) was clear, colorless, and under normal pressure. There with a mild lymphocytic pleocytosis (13 white blood cells and 92% lymphocytes). CSF protein was 63 mg/dL, and glucose was 41.6 mg/dL. He had normal IgG and IgG synthesis rate and negative oligoclonal bands (OCBs). The 14: 3:3 protein was less than 2 ng/ mL, the lactic acid was normal (1.6 nmol/L), and cytology was negative. Serum beta chorio–gonadotrophic hormone (HCG) subunit was 91.42 mIu/mL. Mayo paraneoplastic panel of the serum and CSF yielded negative results. All told, CSF suggested a low-grade inflammatory process. Next, we decided to sample an enlarged periaortic lymph node. Drs. Kattah, Eggers, Dubey, and McKeon Biopsy of a periaortic lymph node showed prominent nonnecrotizing granulomatous inflammation, with an immunostain for CD68 highlighting the many epithelioid histiocytes. Additional stains revealed no evidence of microorganisms. In focal areas, occasional larger cells with clear cytoplasm were identified, although they were largely Key to the initial differential diagnosis here was a normal brain MRI. The principal considerations included a neurodegenerative spinocerebellar disorder, vasculitis involving cerebellar and cochleo–vestibular structures, and in262 Sarah Bach, MD Kattah et al: J Neuro-Ophthalmol 2021; 41: 261-265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Pure tone audiometry. Note bilateral, asymmetric, severe sensorineural hearing loss. High frequencies are affected to a larger extent with inability to hear frequencies greater than 2000 HZ at 60 of greater intensity. The left ear is slightly better. Speech discrimination (not shown) was limited to 12% in the right ear and 58% in the left. obscured by the granulomatous inflammation. These larger cells displayed OCT4 immunoreactivity, confirming the presence of metastatic seminoma (Fig. 3). Drs. Kattah, Eggers, Dubey, and McKeon Given the likelihood of a paraneoplastic syndrome, the patient underwent additional serum testing, including for anti-Ma2, Homer-3, and mGLUR1 receptors, as well as TRIM9, TRIM67, and Adaptor protein-3B2 (3–7). Ultimately, he underwent serologic testing for an autoantibody that has been recently been noted to be present in some patients with seminomas and germinomas, called kelch-like protein-11 antibody. Anti–kelch-like protein-11 was detected by tissue immunofluorescence (Fig. 4) and cell based assays (8). Final Diagnosis Paraneoplastic Kelch-like protein-11 encephalitis associated with metastatic seminoma. DISCUSSION The five-year survival rate in stage 1 testicular seminoma is close to 99%. The diagnosis in this patient preceded by a few months the publication of the novel paraneoplastic Kelch-like protein-11 encephalitis (8,9). The clinical characteristics in our patient were similar to many of the 39 patients in these seminal reports (8,9) in the initial disease description, cochleo–vestibular symptoms were common: vertigo occurred in 21 of 39 patients, and rapidly progressive sensorineural hearing loss was reported in 15 of 39 Kattah et al: J Neuro-Ophthalmol 2021; 41: 261-265 patients, and confirmed in 7 with formal audiological testing (Fig. 2). These characteristics are distinctly uncommon in other paraneoplastic syndromes. To the best of our knowledge, only a handful of paraneoplastic cases previously reported cochlear, vestibular, or cochleo–vestibular impairment (10). Therefore, the kelch–11-like protein antibody, and its association with germ cell tumors, is the most common cause of this neurotological immunophenotype. Previously, the Hu antibody (also known as ANNA-1) was the most frequent antibody found in paraneoplastic acute cochleo–vestibular loss, with small-cell cancer of the lung and thymoma representing the most frequent underlying neoplasms (10,11). Of note, most reported paraneoplastic cochleo–vestibular syndromes—regardless of the antibody or responsible neoplasm—are frequently associated with neurologic abnormalities, an important difference with other isolated nonparaneoplastic autoimmune disorders of the inner ear (12). Probably, the most common cause of sensorineural hearing loss and episodic vertigo is Meniere’s disease (13). However, in Meniere’s, the hearing loss fluctuates, is associated with ear fullness and tinnitus, affect mostly the low frequency sounds, is more frequently unilateral, and is not associated with neurologic abnormalities. The hearing loss in the kelch–11-like protein antibody involves preferentially high-frequency sounds, is bilateral, is gender-specific to men, and has additional neurologic abnormalities (8,9). Ataxia, the second dominant neurologic manifestation in this patient, is common in paraneoplastic neurological syndromes. However, in a 2008 series reviewing common causes of DBN, only 3% of the cases were paraneoplastic (14). In our patient, the combination of oculomotor 263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Biopsy of a periaortic lymph node showed non-necrotizing granulomatous inflammation (B, H&E), with an immunostain for CD68 highlighting the numerous epithelioid histiocytes (A). No microorganisms were seen on special stains (not shown). Higher power magnification of the area in the yellow box in (B) showed occasional larger cells with clear cytoplasm (C, H&E, red arrows), which were largely obscured by the prominent granulomatous inflammation (C, yellow arrow). An OCT4 immunostain (D) highlighted these large cells and enabled a diagnosis of metastatic seminoma. findings suggested flocculus localization (1,2), and the brain MRI was normal. In the previous report, 7 of 39 patients had normal brain imaging, but some others had MRI hyperintensities in the cerebellum, brainstem, and other locations (9). As in our patient, CSF shows modest pleocytosis (an average of 10 white blood cells/mL [lymphocytepredominant]). Our patient did not have elevated CSFexclusive OCBs, and in the initial series of patients less than half (18 of 39) exhibited OCBs (9). The pathological examination in the previous reports revealed “chronic lymphocytic (T-cell predominant) inflammation with non-necrotizing granulomas.” (9) Interestingly, those findings are similar, albeit more pronounced, than those observed in the lymph node biopsy of our patient. Granulomatous inflammation in the original or metastatic seminoma could potentially be misdiagnosed as sarcoidosis (15). Our patient’s neurologic symptoms began insidiously approximately 7 years after the initial diagnosis of testicular seminoma. It remains unclear whether low-grade, subclinical CNS inflammation preceded clinically apparent manifestations in our patient. In one reported case, the neuropathological examination of the cerebellum revealed gliosis and Purkinje cell neuronal loss (9). Retroperitoneal metastatic seminoma and paraneoplastic ataxia developed in 1 patient with quiescent burnt out testicular seminoma (16), indicating that the inciting tumor may be relatively small. In the recent report, among 36 of 39 patients screened for cancer, 21 had testicular seminoma (58%), and 4 had either retroperitoneal neoplasia (including the patient subject of this report) or mediastinal tumors. Some other rare germ cell tumors types were also identified (9). In terms of outcome, 19 of 39 patients stabilized after treatment, 9 of whom improved neurologically (47%). Moreover, those patients detected and treated earlier had better 264 modified Rankin score (mRS) and lower probability of wheelchair dependence. Thus, a better outcomes relates to early identification of cancer and timely treatment, a fact that may become apparent in future prospective studies (Fig 4). Our patient underwent therapy with high-dose methylprednisolone and 5 sessions of plasma exchange (PLEX) while preparing to receive chemotherapy. He received 3 cycles of combination therapy with cisplatin, etoposide, and bleomycin. Sepsis temporarily complicated by sepsis with prolonged hospital stay. He continued to undergo PLEX and 3 consecutive days of high-dose steroids every 6 weeks, in addition to oral prednisone. The latest CT of the chest and abdomen 1 year after completion of treatment showed retroperitoneal node resolution, and the serum beta HCG normalized. The patient benefited from hearing aids, and FIG. 4. Mouse brain tissue indirect immunofluorescence assay representing kelch-like protein-11 patient IgG staining. Punctate binding to near the choroid plexus consistent with staining pattern identified as “sparkles.” Kattah et al: J Neuro-Ophthalmol 2021; 41: 261-265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study the episodic vertigo subsided. The ataxia stabilized, and he was now able to stand and take steps with a walker and assistance to overcome truncal ataxia. The episodic vertigo subsided as well. DBN is mild and does not degrade his normal visual acuity. For maintenance immune therapy, he is on intravenous human immunoglobulin every 6 months and recently received the first course of rituximab (antiCD20 B cell-depleting monoclonal immunosuppressant). This case highlights the need to follow germ-cell tumor patients longitudinally. Baseline testicular ultrasound is often after completion of the initial treatment, with serum markers followed serially; unfortunately, tumor markers such as alpha fetoprotein, placental alkaline phosphatase, and beta HCG have limited utility (17). Neurologic, vestibular, or cochlear dysfunction in germ-cell tumor survivors should raise suspicion for tumor recurrence. In those cases without a previous germcell tumor history, with the suggestive immunophenotype, testing the kelch-like protein-11 antibody can confirm the possibility of an occult germ-cell tumor. The common HLA allele and haplotype associations (DQB1 and HLA DRB1*03:01) are markers that are also amenable to investigation. In conclusion, men with progressive cochlea–vestibular symptoms and progressive ataxia warrant evaluation for paraneoplastic kelch-like protein-11 encephalitis and underlying germ-cell tumor along with investigation of other etiologies listed in the differential diagnosis. Early recognition may make a difference in neurologic and systemic outcomes because many patients will respond to aggressive immunosuppression (8,9). ACKNOWLEDGMENTS This case was presented at the 46th NANOS Meeting. Amelia Island, Florida March 7, 2020. Dr. Joseph C Corbo, MD, (Neuropathology) and Manu Goyal, MD (Neuroradiology) from Washington University in St Louis discussed the case. REFERENCES 1. Shemesh AA, Zee DS. Eye movement disorders and the cerebellum. J Clin Neurophysiol. 2019;36:405–414. 2. Leigh RJ, Zee DS. The Neurology of Eye Movements Oxford New York, NY: New York Oxford University Press, 2015. 3. Hoftberger R, Sabater L, Ortega A, Dalmau J, Graus F. Patient with homer-3 antibodies and cerebellitis. 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