Diagnosis Of Paraneoplastic Limbic Encephalitis Research Articles

Use of PET/CT with 18F-FDG in the diagnosis of paraneoplastic limbic encephalitis

Use of PET/CT with 18F-FDG in the diagnosis of paraneoplastic limbic encephalitis

Paraneoplastic limbic encephalitis in a patient with extensive disease small-cell lung cancer.

Paraneoplastic limbic encephalitis (PLE) is a rare disorder infrequently accompanying malignancy, coexisting in ~50% of the cases with small-cell lung cancer (SCLC). The pathomechanism of PLE is considered to be immune-mediated, with production of specific anti-Hu antibodies and activation of T-cells directed against onconeural antigens present on both tumor cells and neurons. We herein report the case of a 50-year-old male patient who, prior to being diagnosed with SCLC, presented with typical symptoms of PLE (seizures, subacute cognitive dysfunction with severe memory impairment, anxiety and hallucinations). The initial brain magnetic resonance imaging examination revealed mild enlargement and hyperintensity of the hippocampal gyri bilaterally, with narrowed temporal horns of the lateral ventricles; the findings of the cerebrospinal fluid examination were compatible with the diagnosis of lymphocytic meningitis. Due to the suspected infectious origin of the disease, treatment with acyclovir and antibiotics was initially applied. However, following subsequent diagnosis of the underlying SCLC and the presence of antineuronal anti-Hu antibodies in the patient's serum, the diagnosis of PLE accompanying extensive-disease (ED) SCLC was confirmed. In addition to the standard cytotoxic therapy, throughout the course of his disease the patient also continued treatment with valproic acid (VPA) as prophylaxis for the initial seizures. VPA is known to be a potent histone deacetylase inhibitor that may reverse epigenetic changes in tumor cells and potentially improve the outcome of cancer patients. The patient succumbed to the disease 25 months after the diagnosis of malignancy; such a long course is observed in only ~5% of patients with ED SCLC. Therefore, it was hypothesized that the accompanying paraneoplasia and treatment with VPA may have improved the outcome in this patient.

Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis

Encephalitis associated with anti-N-Methyl-D-Aspartate Receptor (NMDAR) antibodies is an autoimmune encephalopathy often associated with teratoma [1]. Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system (CNS) associated with antibodies against aquaporin 4 (AQP4) [2]. Here, we report the case of a patient who developed limbic encephalitis (LE) followed by NMO, whose serum harbored anti-NMDAR and anti-AQP4 IgG antibodies. A 50-year-old woman presented with subacute, shortterm memory loss, confusion, and behavioral changes. Routine blood tests, an infectious disease screening, an electroencephalogram (EEG) and cerebral spinal fluid (CSF) tests were all negative, whereas a brain MRI showed a T2-weighted, hyperintense medial temporal cortex. A pelvic mass was detected by computed tomography (CT) scan. Two months later, she underwent a hystero-adnexectomy with the removal of an ovarian teratoma. A diagnosis of paraneoplastic LE was made. Tests for classical onconeural antibodies (Hu, Ri, Ma2, CV2/CMRP5, amphiphysin, Yo) proved negative. Her memory deficit started to improve 4 months after surgery, when she received repeated courses of low-dose oral steroids. One month later, she had only residual retrograde amnesia (Fig. 1e). Five months later, she developed drowsiness, cervical itching, and impaired gait. Within 2 weeks, she had developed paraplegia and MRI showed multiple T2weighted hyperintense lesions in the pons, hypothalamus, medulla oblongata, and cervical spine (Fig. 1a–c). A CSF analysis proved negative (normal white cell count and proteins, and absence of IgG intrathecal synthesis). Plasmaexchange and high-dose intravenous steroids were initiated, resulting in a slow improvement of strength. Nine months later, she presented with left-eye optic neuritis. High-dose intravenous steroids were partially effective. Three months later, a relapse occurred with weakness of the right limbs. An MRI disclosed new lesions in the pons and dorsal spine (Fig. 1d). Her serum and CSF were tested for AQP4-IgG-Ab by indirect immunofluorescence on a commercial assay (Euroimmun, Lubeck, Germany) [3], proving positive on serum (titer 1:100). The test was extended to NMDAR-IgG-Ab, also proving positive on serum (1:32) and on CSF. The patient was treated with plasma-exchange and oral steroids, with benefit. Three months later, her CSF analysis revealed a normal white cell count and increased protein content (84 mg/dl); matching oligoclonal bands were detected in the CSF and serum. Human leukocyte typing disclosed the presence of the class I allele B8 and class II DR3-DQ2 (DRB1*03-DQB1*02). AQP4-IgG-Aband NMDAR-IgG-Ab-positivity were both confirmed, but a decrease in serum Ab titer was shown (both Abs serum titer 1:10; NMDAR-Ab CSF titer 1:3, 2); VGCC-, AMPAR-, GABAbR-, LGI1and CASPR2-Abs tested negative. Treatment with azathioprine was started. Eight months later, her conditions were stable. This patient presented with LE followed by NMO 1 year later, and tested positive for AQP4and NMDAR-Abs. To M. Zoccarato M. F. Pelizza B. Giometto L. Zuliani (&) Department of Neurology, Ospedale Ca’Foncello, Azienda Unita Locale Socio-Sanitaria 9 Treviso, Piazza Ospedale 1, 31100 Treviso, Italy e-mail: luigizuliani77@gmail.com

A Case of Paraneoplastic Limbic Encephalitis Associated with Small Cell Lung Cancer

Paraneoplastic limbic encephalitis (PLE) is a rare syndrome characterized by memory impairment, affective and behavioral disturbances and seizures. Among many different neoplasms known to cause PLE, small cell lung cancer (SCLC) is the most frequently reported. The pathogenesis is not fully understood but is believed to be autoimmune-related. We experienced a patient with typical clinical features of PLE. A 67-year-old man presented with seizure and disorientation. Brain magnetic resonance imaging demonstrated high signal intensity in the bilateral amygdala and hippocampus in flair and T2-weighted images suggestive of limbic encephalitis. Cerebrospinal fluid tapping revealed no evidence of malignant cells or infection. Positron emission tomography/computed tomography showed a lung mass with pleural effusion and a consequent biopsy confirmed the diagnosis of PLE associated with SCLC. The patient was subsequently treated with chemotherapy and neurologic symptoms gradually improved.

A Case of Paraneoplastic Limbic Encephalitis Associated With Ovarian Teratoma andN-Methyl-D-Aspartate Receptor Antibodies

To the Editor: Paraneoplastic limbic encephalitis (PLE) is a disorder of the nervous system, often the result of malignancy such as lung, ovarian, or testicular tumors.1 Neuropsychiatric symptoms such as mood disturbance, psychosis, cognitive impairment, sleep changes, and irritability are common.2 Psychiatric treatment primarily involves medications to target symptoms such as agitation and hallucinations.3 Despite symptoms such as severe hypoventilation requiring ventilator support, individuals often make a full recovery. The majority of PLE cases have been reported in neurologic or subspecialty psychiatric journals (per a MEDLINE review March 9, 2011, using the keywords paraneoplastic limbic encephalitis for the years 1998 to 2011). We describe the psychiatric and neurologic presentation and management of a patient with PLE associated with mature ovarian teratoma and N-methyl-D-aspartate (NMDA) receptor antibodies. Case report. Ms A, a 25-year-old woman without past medical or psychiatric history, initially presented in 2009 to the emergency department with complaints of near syncope and the following day returned with left temporal headaches, episodic confusion, and memory disturbance. Medical workup including computed tomography (CT) of the head and drug toxicology was unremarkable. She returned to the emergency department on the third day and was admitted to the hospital after complaining of a seizure that was unwitnessed. She was started on treatment with acyclovir 10 mg/kg (for a total dose of 905 mg) for presumed herpes encephalitis and fosphenytoin 18 mg/kg (for a total dose of 1,633 mg) for seizures, but these medications were ultimately discontinued due to negative tests for herpes simplex virus and no further seizures. Electroencephalogram revealed mild-to-moderate disorganized activity with occasional increase in β activity and slow waves, but no epileptiform activity. Magnetic resonance imaging (MRI) of the head showed cerebrospinal fluid (CSF) collection and mass effect on the left hippocampus. Lumbar puncture revealed the following values: 75% lymphocytes, white blood cells (WBCs) 8/mm3, 16% neutrophils, 9% monocytes, red blood cells 2/mm3, protein 42 mg/dL, and glucose 72 mg/dL. A second lumbar puncture 10 days later revealed 92% lymphocytes and WBCs 15/mm3. Three days after discharge (the discharge occurred 3 days after hospitalization), the patient presented to the emergency department with paranoia, hallucinations, and acute agitation. She was admitted to the psychiatric unit for new-onset psychotic disorder not otherwise specified (DSM-IV), although notes indicate the suggestion of “pseudoseizures.” Urine toxicology findings were again unremarkable. The patient was started on risperidone 0.5 mg twice daily, but her condition rapidly deteriorated with drooling, dyskinesias (slapping thighs), poor intake, and decrease in responsiveness despite discontinuation of risperidone after 4 days. She was then transferred to the medical intensive care unit 6 days after admission to the psychiatric unit. In the medical intensive care unit, Ms A had respiratory failure due to aspiration pneumonia and thus was intubated and started on treatment with vancomycin 1 g every 8 hours and piperacillin/tazobactam 3.375 g every 6 hours. Propofol 5 μg/kg/min and dexmedetomidine 0.2–0.7 μg/kg/h were used to manage agitation. She was seen by psychiatric, neurologic, and infectious disease specialists and underwent a battery of tests including ceruloplasmin, cytomegalovirus, cryptococcus, antinuclear antibodies, Epstein-Barr virus, enterovirus polymerase chain reaction, IgM and IgG, mycoplasma, chlamydia, bartonella, rickettsia, influenza, measles, mumps, rubeola, West Nile virus, leptospira, herpes simplex virus types 1 and 2, ova and parasites (stool tests), botulism, microfilaria, and malaria. Findings of a second MRI, magnetic resonance angiography, and single photon emission computed tomography of the head were unremarkable. Negative autoimmune studies included tests for antinuclear antibodies, antineutrophil cytoplastic antibody and antithyroid peroxidase, anti-dsDNA, anticardiolipin, anti-SSA/Ro, anti-SSB/La, and anti-Sm and anti-ribonucleoprotein antibodies. Paraneoplastic workup included CSF studies for anti-CV2, anti-Hu, anti-Ma, and anti-Ta antibodies; voltage-gated potassium channel, NMDA antibodies; collapsin response mediator protein; and acetylcholine receptor, with all tests negative other than that for NMDA receptor antibodies. Subsequent CT and MRI of the pelvis showed a mature teratoma of the left ovary measuring 4.7 cm × 2.7 cm. The patient had recovery with return to baseline shortly after undergoing a left salpingo-oophorectomy. This case illustrates the sudden presentation yet difficult diagnosis of PLE. Treatment resulting in full recovery is not uncommon, particularly with ovarian teratoma. The confusing neuropsychiatric and medical symptoms result in diagnostic confusion with the differential including drug abuse, malingering, and seizure disorders.4 Paraneoplastic limbic encephalitis has also been confused with bipolar disorder.5 False attribution of symptoms to a psychiatric disorder may result in inadequate treatment or delay in seeking medical attention. Patients with PLE may present to the primary care practitioner or general psychiatrist. Therefore, PLE and ovarian teratoma should be considered in young women with encephalitis who present with acute onset of psychiatric symptoms, seizures, autonomic instability, hypoventilation, and dyskinesias.

A Case of Paraneoplastic Limbic Encephalitis during the Course of Depression

To the Editor: A 67-year-old man visited a psychiatric outpatient clinic in October of 2006 after experiencing decreased motivation as well as fatigue. Treatment was initiated following a diagnosis of depression. While physical difficulties such as fluctuating ear ringing and wobbling were apparent, a head CT scan and MRI revealed no irregularities. His treatment regimen consisting of oral administration of milnacipran, 150 mg/day, and alprazolam, 1.6 mg/day, produced limited results. By April of 2007, he was reclusive and experienced increased suicidal feelings, which improved to a certain degree after he was admitted to a psychiatric hospital for 3 months. He lived in stable condition at home after discharge, but his actions and conversation were sluggish. He also experienced unaccountable drowsiness, inability to articulate, dryness of mouth, palpitations, and erections. In July of 2008, he experienced fever outbreak and bloody sputum, and was immediately hospitalized following a diagnosis of pneumonia and cardiac failure. After hospitalization, a chest CT scan revealed enlarged lymph nodes, and biopsy confirmed a diagnosis of lung small cell cancer. On the 29th of the same month during hospitalization, tonic convulsions appeared on the left side of his body along with a concomitant deviation of the eyes to the right. A head CT scan revealed no bleeding. Administration of anticonvulsants and antibiotics brought his condition into remission, but afterward he exhibited cognitive dysfunction and odd behavior, asking questions such as, “Did I die or am I still alive? There’s no oxygen so I wanted to ask.” In a head MRI on the 11th of the same month, T2 weighted image, fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging showed high intensity signals in both the mesial temporal lobe and limbic cortex (Figure 1). There were no findings suggestive of carcinomatous meningitis in CSF obtained by lumbar puncture. Antibodies for various types of viruses were also negative. Steroid pulse therapy was conducted following a diagnosis of paraneoplastic limbic encephalitis. While the frequency of convulsions decreased to some degree, a moderate level of impaired consciousness remained. This was an unusual case in which various neurological symptoms developed over the course of depression, followed by development of lung small cell cancer and a final diagnosis of paraneoplastic limbic encephalitis. Yuichi Onishi Yutaka Shinohara Hirokazu Fujiyama Department of Psychiatry, Tokai University Hachioji Hospital, Isehara, Kanagawa, Japan

Bilateral Temporal Glioma Presenting as a Paraneoplastic Limbic Encephalitis With Pure Cognitive Impairment

Memory impairment caused by bilateral hippocampal primitive brain tumor is rarely reported. Clinical and MRI features can mimic paraneoplastic limbic encephalitis (PLE), and the differential diagnosis between these 2 entities may be difficult. We report the case of a 42-year-old woman presenting with amnesia without neurologic focal signs at clinical examination. The neuroimaging features consisted of bilateral limbic hyperintensities on T2-weighted and FLAIR brain MRI. Despite exhaustive biologic and radiologic investigations, no specific etiology was found. The diagnosis of paraneoplastic limbic encephalitis was suspected, although antineuronal antibodies were negative and no cancer was detected after the first evaluation. Eight months after onset, the memory complaint of the patient increased along with disability in activities of the daily living, the neurologic examination slightly changed with frontal neurologic signs and the brain MRI showed a new cystic lesion in the left hippocampus with enhancement after contrast administration. The left temporal tumor was resected and the neuropathological examination was consistent with gliomatosis cerebri with a focal high grade astrocytoma. This case highlights the need to consider the possibility of infiltrative gliomatosis in patients presenting with features of paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis as a cause of new onset of seizures in a patient with non-small cell lung carcinoma: a case report

IntroductionThe etiology of seizure disorders in lung cancer patients is broad and includes some rather rare causes of seizures which can sometimes be overlooked by physicians. Paraneoplastic limbic encephalitis is a rather rare cause of seizures in lung cancer patients and should be considered in the differential diagnosis of seizure disorders in this population.Case presentationThis case report describes the new onset of seizures in a 64-year-old male patient receiving chemotherapy for a diagnosed stage IV non-small cell lung carcinoma. After three cycles of therapy, he was re-evaluated with a chest computed tomography which showed a 50% reduction in the tumor mass and in the size of the hilar and mediastinal lymphadenopathy. Twenty days after the fourth cycle of chemotherapy, the patient was admitted to a neurological clinic because of the onset of self-limiting complex partial seizures, with motionless stare and facial twitching, but with no signs of secondary generalization. The patient had also recently developed neurological symptoms of short-term memory loss and temporary confusion, and behavioral changes. Laboratory evaluation included brain magnetic resonance imaging, magnetic resonance spectroscopy of the brain, serum examination for 'anti-Hu' antibodies and stereotactic brain biopsy. Based on the clinical picture, the patient's history of lung cancer, the brain magnetic resonance imaging findings and the results of the brain biopsy, we concluded that our patient had a 'definite' diagnosis of paraneoplastic limbic encephalitis and he was subsequently treated with a combination of chemotherapy and oral steroids, resulting in stabilization of his neurological status. Despite the neurological stabilization, a chest computed tomography which was performed after the 6th cycle showed relapse of the disease in the chest.ConclusionParaneoplastic limbic encephalitis is a rather rare cause of new onset of seizures in patients with non-small cell lung carcinoma. Incidence, clinical presentation, laboratory evaluation, differential diagnosis, prognosis and treatment of this entity are discussed.

Encéphalite limbique paranéoplasique avec anticorps anti-RI et séminome médiastinal

We report the case of a 49-year-old man who was admitted for progressive behaviorial disorders with frontal elements. There was no sensorial nor motor deficiency. Clinical examination revealed android obesity, cutaneous and mucous paleness, pubic and axillary depilation and gynecomastia. Encephalic MRI found a lesion of the left amygdalian region with high T2 intensity and low T1 intensity associated with gadolinium-enhancement. Cerebrospinal fluid analysis showed a lymphocytic meningitis. Panhypopituitarism was found on the endocrine investigations. Anti-RI antibodies were positive, leading to the diagnosis of paraneoplastic limbic encephalitis. The CT-scan showed a node of the lower part of the thymic area. Surgical resection revealed an ectopic mediastinal seminoma. The evolution consisted of paraneoplastic fever and crossed-syndrome with right hemiparesia and left common oculomotor nerve paralysis. Treatment was completed by two cycles of carboplatin, corticosteroids and substitutive opotherapy. Paraneoplastic fever disappeared, but behavioral disorders and palsy remain unchanged. The patient died two years later in a bedridden state. This case of paraneoplastic limbic encephalitis associated with positive anti-RI antibodies and mediastinal seminoma is exceptional and has not to our knowledge been described in the literature. Cancers usually associated with anti-RI antibody are breast and lung cancer. Paraneoplastic limbic encephalitis is not the classical clinical presentation, which usually is brainstem encephalitis. Hypothalamic involvement, uncommon in paraneoplastic limbic encephalitis is mainly associated with positive antineuronal anti-Ma2 antibodies. Finally, the gadolinium enhancement on encephalic MRI is unusual in paraneoplastic limbic encephalitis.

Focal paraneoplastic limbic encephalitis presenting as orgasmic epilepsy

To report orgasmic epilepsy as a manifestation of paraneoplastic limbic encephalitis in a patient with small cell lung cancer. A 57 years-old woman presented with 2 month history of daily spells that consisted of a sudden pleasure provoking feeling described 'like an orgasm' lasting for 30 s to 1 min. She was a heavy smoker and had noted recent weight loss. Bronchial biopsy, following the finding of a right lung mass, confirmed the diagnosis of small cell lung cancer (SCLC). Spells subsided after starting carbamazepine. The lung cancer was treated with chemotherapy and chest radiation therapy resulting in a complete radiologic response. Brain magnetic resonance imaging (MRI) revealed left temporal lobe area of increased signal on T2 and FLAIR sequence. T1-weighted images after contrast administration demonstrated a circumscribed area of enhancement in the left anterior medial temporal lobe. Electroencephalogram (EEG) showed focal left mid-temporal sharp waves and intermittent slowing. Anti-Hu antibodies were detected in her serum supporting a diagnosis of paraneoplastic limbic encephalitis as the cause of her orgasmic epilepsy. The patient has been followed for 2 years after treatment without tumor recurrence or neurological deterioration. Orgasmic epilepsy is another mode of presentation of paraneoplastic limbic encephalitis leading to the diagnosis of an occult SCLC. EEG and MRI findings suggest that in this case the seizures originated from the left hemisphere. It is possible that early recognition and treatment of the SCLC will improve the prognosis of this neurologic entity.

Paraneoplastic limbic encephalitis—case report and review of literature

We report a 77-year old man who presented with a sub-acute dementia associated with aggressive behaviour, ataxia, rapid progression and death. No cause for his illness could be detected in his lifetime, but at post mortem he was found to have paraneoplastic limbic encephalitis and a bronchogenic tumour. A diagnosis of paraneoplastic limbic encephalitis should be considered in the differential diagnosis of unexplained dementias and appropriate investigations performed to diagnose the condition.

Serial 18F-fluoro-2-deoxy-D-glucose Positron Emission Tomography and Magnetic Resonance Imaging of Paraneoplastic Limbic Encephalitis

To review and expand the existing literature of magnetic resonance imaging (MRI) and positron emission tomography (PET) of paraneoplastic limbic encephalitis (PLE). We performed serial MRI and 18F-fluoro-2-deoxy-D-glucose (FDG)-PET in a patient with anti-Ma2-positive PLE. In addition, we reviewed the relevant literature by conducting a search in the Medline database. We found a total of 7 published patient studies of possible or probable PLE containing both MRI and PET data. In 1 of these reports, the diagnosis of PLE can be regarded as proven. The results of the previous studies are controversial. Epileptic activity and inflammation are assumed to be underlying mechanisms of increased FDG uptake. In our study, we found a focal tracer accumulation in the left medial temporal lobe, which increased during the first 9 months of follow-up and corresponded with an increase of serum anti-Ma2 antibody titers. The MRI findings showed a hyperintense signal change in the left medial temporal lobe without contrast enhancement, which remained unchanged over time. The results of functional and structural imaging in PLE may differ substantially. Results of FDG-PET can demonstrate focal hypermetabolism over a long time, which may indicate therapeutic potential. A prospective study with more patients will be needed to clarify the relevance of PET as a possible outcome measure in PLE. Future studies should include scalp or semi-invasive electroencephalographic recordings during PET acquisition.

Paraneoplastische limbische Enzephalitis bei kleinzelligem Bronchialkarzinom

We report about a 63-year-old male patient who complained of a recent onset of confusion. A mediastinal mass had been detected in his chest X-ray three days before admission to our clinic. Surprisingly, a CT scan of the brain revealed no signs of cerebral masses or oedema. MRI demonstrated bright hyperintens signals in the medial aspect of both temporal lobes. Biopsy by mediastinoscopy showed small cell lung carcinoma (SCLC). No distant metastases were found by staging procedures. Cerebrospinal fluid and serum contained antineuronal antibodies (anti-Hu). The combination of symptoms, MRI findings and paraneoplastic antibodies established the diagnosis of paraneoplastic limbic encephalitis in a patient with SCLC. Chemotherapy combined with immunosuppression by corticosteroids was started immediately. The primary tumour responded to therapy but improvement of cerebral symptoms was unsatisfactory. Severe memory loss and personality changes remained unchanged while there was a slight improvement in confusion and hallucinations.

Paraneoplastic limbic encephalitis

Paraneoplastic limbic encephalitis (PLE) is a rare neurological consequence of a variety of cancers, most commonly originating from lung, breast and testis. The aetiology is believed to be immune-mediated, caused by tumour-induced autoimmunity launching an attack against one’s own central nervous system. The patient may present with amnesia, depression, anxiety, seizures and/or personality changes. The onset of these symptoms may precede the diagnosis of malignancy by a period of up to 2 years. The malignancy may be occult and unless the syndrome is recognised, it may fail to be detected. The diagnosis of PLE is suggested by the clinical picture, MRI evidence of mesial temporal lobe abnormality and CSF abnormalities such as the presence of oligoclonal bands. It may be further supported by the presence of paraneoplastic antibodies in the serum. Immunosuppression has been tried in some cases but memory impairment is often irreversible. There are several case reports in the literature of paraneoplastic limbic encephalitis but few emphasise the resulting impact that this may have on the patient’s quality of life and their carers. The accompanying amnesia is often far more distressing to the carers, who are aware of the limitations of treatment of the underlying malignancy. Hospices offer the appropriate palliative environment for such patients as well as physical and psychological respite to the carers.

Paraneoplastische limbische Enzephalitis

We report on a 69-year old male patient who presented with vague depressive symptoms and loss of weight accompanied by lack of appetite, ageusia and anosmia. The patient died of bronchial pneumonia, and neuropathological examination revealed a so-called limbic encephalitis. The paraneoplastic origin of this case was later confirmed by discovery of a clinically inapparent, indolently growing small cell lung cancer. This case illustrates the difficult clinical diagnosis of paraneoplastic limbic encephalitis and the need for a close cooperation of pathologists and neuropathologists in the clarification of such cases.