A Rare Presentation of Paraneoplastic Striatal Encephalitis Associated with Nonsmall Cell Lung Cancer

Paraneoplastic striatal encephalitis (PSE) is relatively unusual, accounting for only 1% of all paraneoplastic neurological syndromes.1 PSE is usually found in association with the presence of onconeural anti‐CV2/collapsin response mediator protein (CRMP) 5 (64%) and/or anti‐Hu antibodies1, 2 and small cell lung cancer.1, 2, 3 Hyperintensity in the basal ganglia (BG) is often evident on T2‐weighted and fluid attenuated inversion recovery (FLAIR) sequences in magnetic resonance imaging (MRI).1 Herein, we report a case of “antibody negative” PSE as the initial presentation of nonsmall cell lung cancer (NSCLC).

Case Report

A previously well 67‐year‐old male was admitted with a 3‐week history of dysarthria, oral sensory change, and neck pain. Recent functional decline was reported by his family, with fluctuating amnesia, agitation, and somnolence. He worked as a farmer and was a current smoker (50 pack‐years). Examination showed orofacial dyskinesias and cervical chorea.

Computed tomography (CT) scan of the brain revealed no acute abnormalities. Serological work up for infective causes (Cytomegalovirus (CMV), Epstein‐Barr virus (EBV), syphilis, toxoplasmosis, Borrelia burgdorferi, parvovirus, leptospirosis, brucella) were all negative. Cerebrospinal fluid (CSF) analysis was normal (cytosis, (2cells/uL); protein content, 0.44g/L; glucose 4.5mmol/L). CSF culture and polymerase chain reaction testing (Herpes simplex virus 1, Herpes simplex virus 2, Human Herpesvirus 6, Varicella‐zoster virus, CMV, EBV) were negative. Oligoclonal bands were positive (CSF Immunoglobulin G (IgG) 0.085g/L).

MRI of the brain revealed diffuse bilateral hyperintense T2/FLAIR signal involving the putamen and caudate nuclei without evidence of cortical ribboning or restricted diffusion (Fig. 1A–F). Metabolic, autoimmune, and toxin screens were unremarkable. Because of the clinical concern for PSE, a CT of the chest, abdomen, and pelvis was performed, revealing right hilar adenopathy (station 11R) and right lower lobe consolidation (Supplemental Figure S1). The patient's clinical condition deteriorated rapidly, with increasing agitation and restlessness. On day 10, he developed paranoia and symptoms of acute psychosis. He was transferred to the intensive care unit for supportive management and commenced on high‐dose methylprednisolone (1000 mg/kg/day) for 5 days with concurrent intravenous immunoglobulin. A paraneoplastic antibody work up (anti‐Yo, anti‐Hu, anti‐Ri, anti‐Ma1, Ma2, anti‐CV2/CRMP5, anti‐amphipysin, anti‐Sox‐1, anti‐Zic‐14, anti‐Tr, anti‐CASPR2, anti‐glutamic acid decarboxylase (GAD), anti‐LgI1, anti–N‐methyl‐d‐aspartate receptor) was negative.

Figure 1.

T2 hyperintense signal change on fluid attenuated inversion recovery imaging involving the caudate and putamen nuclei bilaterally (A). Signal within the right and left thalamus is within normal limits. There was no evidence of cortical ribboning or restricted diffusion on diffusion weighted imaging (B,C). Follow‐up imaging at 3 weeks revealed more intense T2 signal change on fluid attenuated inversion recovery imaging (D) within the caudate and putamen (arrow). Again, no evidence of cortical ribboning or restricted diffusion is identified on diffusion weighted imaging (E,F). Repeat magnetic resonance imaging brain at 7 weeks (G–I) demonstrates significant improvement with reduced bilateral T2 hyperintense signal abnormality within the basal ganglia (caudate and globus pallidus) on T2 fluid attenuated inversion recovery imaging (G). No gradient abnormality or hemosiderin deposition is noted in this region (H,I).

Serial MRI imaging revealed significant improvement (Fig. 1G–I), but his neurological symptoms deteriorated. His clinical course was complicated by recurrent episodes of aspiration pneumonia and severe agitation. He was transferred to a tertiary centre for escalation of treatment and commenced plasmapheresis (5× cycles) and rituximab (1× cycle). Persistent suspicious adenopathy on CT (Supplemental Figure S1) prompted endobronchial ultrasound guided transbronchial needle aspiration of a right hilar lymph node, station 11R, which confirmed adenocarcinoma (TTF‐1 positive), consistent with NSCLC. His clinical condition continued to decline, and he died 4 weeks after receiving palliative radiotherapy to the right hilum.

Discussion

Previous reported cases of PSE are uncommon.2, 3, 4, 5, 6 Most have occurred in association with anti‐CV2/CRMP52, 3, 6 onconeural antibodies and small cell lung cancer.2, 3, 4, 5, 6 NSCLC, non‐Hodgkin's lymphoma, and renal cell carcinoma are also described.2 Clinical presentation is variable, often mimicking other disorders.1, 7 Patients are older (>40 years)1 presenting with subacute onset of abnormal movements2, 3 associated with subtle neurological features such as cognitive impairment,2, 5, 6 agitation,2, 5, 6 altered behavior,2, 6 and emotional labiality.2, 6

The pathogenesis is not fully understood but is thought to involve an immune‐mediated response directed against neural antigens that are abnormally expressed in the tumor.7, 8 These onconeural antibodies are directed against intracellular or extracellular antigens and are found in 80% of patients with paraneoplastic movement disorders.1, 8 For intracellular antigens, the presence of IgG onconeural antibodies in the serum and CSF are largely nonpathogenic and considered epiphenomena. They are indicative of neuron directed immunity and valuable in diagnosis, but not responsible for cell death.8, 9 Rather, the underlying pathological process of severe neuronal loss likely involves cytotoxic CD8+ T cells3, 5, 8, 10 with an inflammatory reaction causing neuronal dysfunction and irreversible cell death.3 As such, our patient showed radiological improvement posttreatment (Fig. 1G‐I), but no neurological recovery. Overall, response to immunosuppressive treatments and chemotherapy is poor2, 3, 6 and where feasible treatment of the underlying malignancy is the treatment of choice.8 For extracellular antigens, humoral mechanisms dominate, causing disruption of synaptic transmission and typically respond better to immunosuppressive treatments and have better clinical outcomes.8, 9, 10

No detectable onconeural antibody was found in this case, but the patient satisfied published diagnostic criteria,9 and although we did not find one, this is not to suppose that one did not exist.7 Some are likely not yet discovered and others (eg, anti‐ gamma aminobutyric acid A receptor (GABA_AR) antibodies were unable to be tested at our institution.

Our patient demonstrated striking changes in the BG. Similar, but less pronounced T2 hyper‐intense signal abnormality have been shown in previous reports.2, 3, 4, 5, 6 However, a normal MRI does not exclude a diagnosis of PSE,1 and these changes have a broad differential diagnosis requiring careful interpretation in the context of the patient's clinical history, presentation, and laboratory findings.11 Table 1 illustrates the differential diagnosis of these BG abnormalities, including their clinical, radiological, and laboratory features.

Table 1.

Differential diagnosis in adults of T2H of the BG on MRI

Differential Diagnosis*	Clinical Findings	Typical Imaging Findings: MRIa	Laboratory Features
Metabolic
Hyper‐ammonemia (acute)	History of liver disease, acute presentation with jaundice, encephalopathy. May lead to coma/death Precipitants: infection, GI bleed, constipation, renal failure	Symmetrical bilateral, T2H: BG, insular cortexb and cingulate gyrus	Evidence of decompensated liver disease Elevated serum ammonia levels
Hypoglycemia	Altered consciousness, seizures, LOC, coma Focal neurological deficits, paresthesia Diabetics, accidental overdose	T2H: BG, cerebral cortex, hippocampi Sparing of thalamus, brainstem, & cerebellum	Low serum glucose (<3.9 mmol/L) Increased serum C‐peptide (insulinoma)
Hypoxic ischemic encephalopathy	Acute presentation with history of anoxia, near drowning, arrest, asphyxiation, or cerebral hypo perfusion event	T2H: BG, striatum and cortex (diffuse). Restricted diffusion on DWI (acute)	Hypoxia Lactatemia
Wilson's disease	Associated with liver disease, Kayser‐Fleischer rings, behavioral change, neuro‐psychiatric symptoms, onset <40 years	T2H: putamen, GP. Midbrain “Face of giant panda sign” on T2W	Low serum ceruloplasmin
Wernicke's encephalopathy	Triad of confusion, ataxia, and ophthalmoplegia ±cognitive impairment & confabulation History of alcohol abuse, malnutrition/malabsorption	Symmetrical T2H: BG, mammillary bodies, medial thalami, periaqueductal gray matter	Characterized by thiamine deficiency Vitamin B1 assay
Extrapontine myelinolysis	Rapid correction of sodium Quadriplegia, pseudobulbar symptoms	T2H: putamen, GP, thalami with T1 hypointense signal	Electrolyte abnormality, serial sodium (Na)
Toxins/poison
Organo‐phosphates	History of exposure Cholinergic crisis, muscle weakness, paralysis, extrapyramidal symptoms	Symmetrical T2H: BG‐ putamen and caudate	Clinical diagnosis
Carbon monoxide	Exposure (fire, poor ventilation) Headache, seizures, altered consciousness Delayed NPS: Cognitive decline, abnormal gait, personality change	Bilateral T2H: globus pallidus, caudate, white matter changes (centrum semiovale periventricular)	Elevated serum level carboxyhemoglobin
Methanol	History of exposure: accidental or intentional Visual disturbance/optic neuritis	Symmetrical T2H: BG, putamen (can be hemorrhagic)	Metabolic acidosis Raised anion & osmolar gap
Inflammatory
Nonparaneoplastic autoimmune encephalitis	Younger, female predominance Gradual anterograde memory loss, psychiatric symptom, seizures. Can be associated with autoimmune conditions: SLE	T2H: BG, medial temporal lobes, limbic systems, maybe normal	Various neural antibodiesc (serum and CSF; ie, anti‐NMDA‐R, anti‐VGKC) Anti‐dsDNA, ANA (SLE)
Vasculitis (Neuro‐Behcet)	History of ulcers, uveitis Middle eastern/Japanese Headaches, personality change, dysarthria, cerebellar signs	T2H: BG, bilateral (33%), surrounding oedema, brainstem, thalamus	Nonspecific HLA‐ B51 is associated
Paraneoplastic encephalitis	Associated with underlying malignancy, may predate diagnosis. Variable presentation: onconeural antibodyd	T2H: BG, mesial temporal lobes, limbic systems	Onconeural antibodiesc (serum/CSF, ie, anti‐Hu, anti‐CV2/CRMP5, anti‐Yo)
Infectious
Viral encephalitis	Acute onset fever, headache, focal neurological deficits, seizures, altered LOC Psychiatric symptoms are uncommon	T2H: cortex (temporal, frontal), BG, thalamus	PCR of CSF: identify viral pathogen Pleocytosis CSF Antibody detection
Toxoplasmosis	New focal neurological symptoms, fever, headache Immunocompromised patient	Multiple, variable T2 intensity lesions: BG, gray–white matter junctions, perilesional oedema	T. gondii IgG, IgM antibodies CSF PCR: T.gondii
Neurodegenerative
CJD	Rapidly progressive dementia, myoclonus, psychiatric symptoms ± cerebellar signs Mostly sporadic (80%–90%)	T2H: BG (caudate and putamen), Cortical ribboning Restricted diffusion on DWI	S‐100 CSF 14‐3‐3 protein EEG Brain biopsy
Neoplastic
Primary CNS lymphoma	Progressive: headache, focal neurological signs, seizures, personality change, >50 years Male predominance	Variable T2 signals Low grade more likely in BG	Not helpful
Vascular
DCVT	Acute headache, nausea, vomiting, seizures, coma Risk factors for VTE	Bilateral T2H: thalamus, BG Hyperintense thrombuse	Thrombophilia screen Vasculitis screen
Arterial occlusion	Sudden agitation, obtunded, coma, behavioral changes ± risk factors for stroke	T2H: thalamus, BG Restricted diffusion on DWI	Not helpful acutely

^*Diseases presenting in childhood such as mitochondrial diseases are not included.

^aRefer to appearance on T2‐weighted magnetic resonance imaging.

^bWhere relevant, areas on MRI that are more frequently involved are in italics.

^cExamples only; list is not exhaustive.

^dAntibodies largely against intracellular antigens correlate to cause and pattern of involvement.

^eMagnetic resonance venogram may be required.

T2H, T2 hyperintense signal abnormality; BG, basal ganglia; MRI, magnetic resonance imaging; GI, gastrointestinal; DM, diabetes mellitus; LOC, loss of consciousness; DWI, diffusion weighted image; GP, globus pallidus; NPS, neuropsychiatric symptoms; SLE, Systemic lupus erythematosus; CSF, cerebrospinal fluid; NMDA, N‐methyl‐d‐aspartate; VGKC, voltage gated potassium channel; dsDNA, double stranded DNA; ANA, antinuclear antibody; HLA, human leukocyte antigen; CV2/CRMP5, Collapsin response mediator protein; PCR, polymerase chain reaction; T. gondii, toxoplasma gondii; IgG, Immunoglobulin G; IgM, Immunoglobulin M; CJD, Creutzfeldt‐Jakob disease; EEG, electroencephalography; CNS, central nervous system; DCVT, deep central venous thrombosis; VTE, venous thromboembolism.

To conclude, the acute onset of movement disorder, cognitive impairment, and agitation with T2 signal hyperintensity in the BG on MRI should prompt a search for an underlying malignancy, as best outcomes are likely in those who receive early and aggressive primary tumor treatment.

Author Roles

(1)Manuscript Preparation: A. Writing of the first draft, B. Review and re‐edit, C. Image preparation, D. Table preparation, E. Review and Critique, F. Final draft preparation.

A.O.: 1A, 1B, 1C, 1D, 1F

R.D.: 1B, 1E

O.T.: 1E

B.J.S.: 1B, 1D, 1E, 1F

M.P.K.: 1B, 1C, 1E, 1F

M.F.: 1B, 1C, 1D

R.M.: 1B, 1E, 1F

G.P.: 1B, 1E, 1F

J.P.C.: 1B, 1D, 1E, 1F

Disclosures

Ethical Compliance Statement

As this is a case report, it was exempt from institutional board review, but complied with good clinical practice guidelines. Informed written consent in English was obtained from the patient's next of kin. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months

The authors declare that there are no additional disclosures to report.

Supporting information

Figure S1. Axial computed tomography (CT) of the thorax with contrast (A) shows enlarged hilar lymph nodes at station 11R (arrow), which persist on follow‐up imaging at 6 weeks (B). Consolidation with air bronchograms (asterisk) of the left (A) and right (B) lower lobes is shown. AA, ascending aorta; PA, pulmonary artery; SVC, superior vena cava.