Anti-Ta-associated encephalitis is a paraneoplastic inflammatory brain disorder with immune-mediated neurological symptoms. The well-characterised onconeuronal antibody, anti-Ta, reacts with the paraneoplastic protein PNMA2 (former antibody name: anti-Ma2). ¹ Neurological symptoms often include abnormalities in eye movement, short-term memory loss, seizures, irritability, personality change or confusion.^2,3 The symptoms tend to precede tumour diagnosis and are often more debilitating than the malignancy itself.² The first study of anti-Ta-related paraneoplastic encephalitis reported 10 young men with testicular cancer.³ Other tumours occur in females⁴ and approximately 30 cases have been reported.^2,5 Several tumours express the protein that, in healthy adults, is restricted to brain and testicular germ cells.³ In contrast to other paraneoplastic syndromes, a remarkable number of patients show neurological improvement if the underlying tumour allows complete surgical resection.² We report a patient’s history of anti-Ta-associated neurological syndrome with atypical parkinsonism and massive rigidity due to occult testicular cancer.

Case report

In 2001, a 66-year-old man suddenly developed disorientation, restlessness, psychomotor agitation and fever. A bradykinetic syndrome with rigidity was noted. Verbal output was reduced and the patient responded only in short sentences. Head CT and lumbar puncture examinations were normal, and EEG demonstrated a right temporal epileptic focus.

After 2 weeks, the patient was admitted to the Department of Neurology, Charité, University Medicine Berlin, Berlin, Germany, with further neurological deterioration. He was drowsy, with markedly reduced verbal output, and only occasionally followed simple instructions like closing the eyes. He had mask-like facies, rigidity of the trunk and limbs, and leg reflexes were absent. Pupillary responses were normal, but eye fixation was impaired and he could not perform smooth-pursuit eye movements. However, vestibulo-ocular reflexes were intact and there was no gaze palsy. Babinski’s sign was negative, but primitive reflexes like palmomental reflex, grasp and root reflex, pursing reflex and non-habituating glabellar sign were present.

Laboratory examinations of blood and urine showed no abnormalities, cerebrospinal fluid showed elevated protein, normal glucose, no pleocytosis or immunoglobulin synthesis. Cerebral MRI (fig 1A) showed generalised atrophy with periventricular leucoencephalopathy without contrast enhancement. Body CT and abdominal ultrasound examinations showed no suspicious masses.

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Figure 1

 T2-weighted, axial MRI slices (A) at the time of admission and (B) after 3 months. (A) The initial MR study already showed cortical and subcortical atrophy, indicated by enlarged sylvian fissures and ventricles. (B) A further increase in size with respect to the anterior horns of the lateral ventricles is noted (arrows), indicating progressive atrophy. Microangiopathic lacunar lesions are depicted in both studies (small arrows) without significant progression. (C) High-magnification photograph (×400) of testes showing seminiferous tubules with disturbed spermatogenesis (H&E-stained slice). (D,E) Immunohistochemistry for placental-like alkaline phosphatase (PLAP) highlighted multiple bilateral microscopic tumour cells with remarkably enlarged nuclei and clear cytoplasm (arrows).

After 3 months, he deteriorated neurologically and opened his eyes only to painful stimuli. He had low-grade fever and tachycardia, and profuse sweating without any signs of infection. The neurological examination revealed an akinetic-rigid syndrome, bilateral ptosis, slow pupillary response, and he was unable to fixate. Eye movements were conjugate with absent oculocephalic reflex. He had generalised muscular atrophy and absent reflexes. A new MRI displayed marked progression of the general cerebral atrophy (fig 1B).

Anti-Ta antibodies were detected, while other onconeuronal antibodies such as anti-Hu, anti-Yo, anti-Ri, anti-GAD, anti-amphiphysin, anti-CV2 and anti-PNMA1 antibodies were negative. The anti-Ta antibody together with the compatible neurological symptoms proved a paraneoplastic origin and expedited the search for a malignancy. Endoscopy, body 2(fluorine 18)fluoro-2-deoxy-d-glucose positron emission tomography, repeated body CT examination and bone marrow biopsy revealed no neoplastic changes. Genitourinary examination was normal as well as tumour markers PLAP, α-fetoprotein and β human chorionic gonadotrophin. Testicular ultrasound examination revealed homogeneous echo pattern, no atrophy and no masses suspicious for malignancy.

Because of life-threatening neurological deterioration, the patient’s wife consented to bilateral orchiectomy. The original pathological evaluation was negative for testicular malignancies, but detailed review using PLAP-stained slides verified multiple bilateral microscopic intratubular germ-cell neoplasia (fig 1C–E).

At 10 days after surgery, the patient was awake, displayed spontaneous eye opening, responded when his name was called, followed simple instructions, and focused objects. The rigidity was markedly reduced enabling the patient to extend his limbs. Grasp and root reflex, pursing reflex and non-habituating glabellar sign disappeared. After 4 months he used up to six words and recognised his relatives.

The patient was admitted to a nursing home and had long-term stabilisation. He died from pneumonia 18 months later, and no autopsy was obtained.

Comment

We report a patient’s history of anti-Ta-associated paraneoplastic neurological syndrome (PNS) with an occult testicular malignancy despite unsuspicious tumour diagnostics. Our patient developed atypical parkinsonism with a severe hypokinetic syndrome, striking reduction of verbal output, and massive rigidity, thereby supporting the findings in five patients of a previous report that parkinsonian-hypokinetic features seem to happen more frequently with anti-Ta encephalitis than with other PNS.² Regarding the revised criteria for PNS, the presence of the well-characterised anti-Ta antibody together with the appropriate clinical and imaging findings in our patient fulfils the requirements for definite PNS.⁵

The decision for orchiectomy without tumour detection was based on (1) life-threatening deterioration, (2) the remarkable number of patients with neurological improvement after tumour resection in cases of anti-Ta-associated encephalitis, (3) the absence of suspicious masses using magnetic resonance, CT, positron emission tomography and endoscopic imaging and (4) the high frequency of testicular cancer in patients with anti-Ta-associated PNS. At the time of presentation, all previously reported cases with anti-Ta encephalitis had testicular neoplasms.³ Up to now, other tumours were found in females to cause Ta-associated paraneoplastic encephalitis.⁴ The underlying mechanisms are thought to consist of tumour proteins triggering an autoimmunological response against the nervous system.³ The first neurological symptoms of our patient preceded tumour diagnosis by about 6 months, which is the median time in the original report on anti-Ta antibodies.³

A special feature of anti-Ta-related paraneoplastic encephalitis is the response to therapy. This could be partly explained by testicular malignancies that respond better to treatment than breast or lung tumours.² After orchiectomy, our patient had improvement in the neurological symptoms including alertness, spontaneous eye opening, following simple instructions, focusing objects and using a few words. Moreover, the rigidity of all extremities was markedly reduced and most primitive reflexes disappeared.

Given that the immunohistochemical staining in this case revealed microscopic tumour despite unsuspicious findings in repeated testicular ultrasonographic examination, the presence of anti-Ta antibodies together with appropriate clinical findings should prompt every effort to find an underlying malignancy. This case underscores the high specificity of anti-Ta antibodies. According to the new diagnostic criteria, six PNS defining reactivities were identified so far,⁵ among which anti-Ta is the most recently identified. One has to keep in mind that failure to make premortem tumour detection is common, also due to possible anti-cancer effects of the immune response, reducing tumour enlargement and metastasis. This case demonstrates that even resection of healthy-appearing tissue might, in exceptional cases, be necessary and justified, if extensive investigation failed to demonstrate tumour masses.