Pearls & Oy-sters: Rapidly progressive dementia

PEARLS

• Voltage-gated potassium channel (VGKC) antibody–associated encephalitis is a well-known form of limbic encephalitis characterized by acute to subacute onset of confusion and cognitive impairment, mediotemporal seizures, and psychiatric disturbances.

• Among other causes of rapidly progressive dementia, this condition is responsive to immunotherapy, and therefore correct and early diagnosis is crucial.

• Sporadic Creutzfeldt-Jakob disease (sCJD) typically presents with rapidly progressive dementia associated with a mixture of cerebellar, extrapyramidal, visual, behavioral, or psychiatric symptoms.

OY-STERS

• VGKC antibody–associated encephalitis may be confused with sCJD due to overlapping of clinical, neuroradiologic, and biochemical features; careful and complete medical evaluation is imperative in order to prevent potential misdiagnosis of a reversible condition for a terminal one.

CASE REPORT

A 65-year-old woman was admitted after a 4-month history of rapidly progressive cognitive impairment. Her medical history was unremarkable without history of cigarette smoking, alcohol abuse, or neurologic or psychiatric illness. She was able to perform all activities of daily living until 4 months prior to evaluation, when she developed unusual behavior and memory impairment. She also complained of malaise and fatigue. Two months prior to evaluation, she began to have difficulty with her daily activities, developed depression, and developed more severe behavioral and memory problems. She was seen by a psychiatrist and underwent a brain MRI, which did not demonstrate any abnormalities. By the time she presented for neurologic evaluation, she had developed confusion and was unable to take care of herself. Due to the rapid progression of symptoms, the patient was admitted for further investigation.

Neurologic examination demonstrated no cranial nerve or sensory deficits. There was no weakness present but the patient did have extensor plantar responses bilaterally. Mini-Mental State Examination score was 19/30 (temporal and spatial disorientation with verbal learning impairment) and extensive neuropsychological assessment confirmed impairment of language (verbal fluency and naming), memory, and selective attention. The patient was also found to have fluctuations of consciousness as well as hallucinations. EEG demonstrated a background pattern of 7–8 Hz and slow biphasic and triphasic waves with higher amplitude in frontal regions (figure, A). A few days after admission, the patient developed faciobrachial tonic seizures and generalized tonic-clonic seizures. The severity and frequency of seizures, as well as the EEG abnormalities (figure, B), improved after treatment with levetiracetam. Neuropsychological features, however, remained unchanged. Standard blood examinations were normal. Blood tests were also negative for lupus anticoagulant, antinuclear antibodies, antibodies to extractable nuclear antigens, antineutrophil cytoplasmic autoantibodies, anticardiolipin antibodies, and cryoglobulins. Serum neoplastic markers and angiotensin-converting enzyme were within normal range.

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Figure EEG and MRI

EEG recordings show diffuse slowing with slow biphasic and triphasic waves with higher amplitude on frontal regions (A). EEG recording after oral treatment with levetiracetam shows the resolution of these waves (B). Brain MRI at admission: axial T2-weighted and diffusion-weighted imaging sequences demonstrate hyperintense areas involving the left striatum (C, D, arrow). Coronal FLAIR with hyperintensity of the right hippocampal cortex (E, arrow). Apparent diffusion coefficient map reveals normal diffusion coefficient in right caudate (F, circle 2) and restricted diffusion in left caudate and putamen (F, circle 1).

Fluid-attenuated inversion recovery (FLAIR), T2-weighted, and diffusion-weighted imaging (DWI) MRI revealed areas of hyperintense signal involving the right hippocampal cortex and left striatum (figure, C–E). Comparison with the apparent diffusion coefficient (ADC) map revealed restricted diffusion in the left caudate and putamen (figure, F). CSF cell count and total proteins were normal; isoelectric focusing showed oligoclonal bands in serum and CSF. Serum and CSF antibodies against Borrelia burgdorferi and Treponema pallidum and CSF culture for bacteria and fungi were negative. CSF and blood nPCR assays were negative for herpes simplex virus 1 and 2, cytomegalovirus, HIV, Epstein-Barr virus, human herpesvirus 6, varicella-zoster virus, parvovirus B19, measles virus, adenovirus, and enteroviruses.

CSF examination revealed a markedly increased total tau protein (>1,200 pg/mL) and a positive 14-3-3 protein test. The level of the latter was calculated semiquantitatively by Western blotting, as described.¹ Densitometric value of the 14-3-3 band in the patient was 5-fold higher than that of the internal control sample (non-CJD subject who had trace levels of 14-3-3 protein) and comparable to that of a typical sCJD case with methionine homozygosity at codon 129 in the prion protein gene (PRNP) and pathologic prion protein type 1 (MM1 type) confirmed at autopsy. PRNP analysis revealed methionine/valine heterozygosity at the polymorphic codon 129. Total body CT imaging, esophagogastroduodenoscopy, colonoscopy, and gynecologic evaluation were normal.

IV immunoglobulin (0.4 mg/kg/d for 5 days) and steroids (methylprednisolone 1 g/d for 5 days) were administered, followed by a course of oral corticosteroids (50 mg/d oral prednisolone). Three weeks later, the patient's clinical condition began to improve and brain MRI showed partial resolution of the FLAIR, T2, and DWI hyperintensities in the right hippocampal cortex and left striatum. One month later, serologic evaluation revealed VGKC/leucine-rich glioma-inactivated 1 (LGI1) autoantibodies. Screening for other autoantibodies, including onconeural antibodies (Hu, Yo, Ri, CV2, amphiphysin, Ma2) and autoantibodies against neuronal surface antigens (AMPAR, NMDAR, CASPR2), was negative.

Three months after her initial presentation, a second cycle of IV immunoglobulin and steroids followed by oral corticosteroids was administered. The antiepileptic therapy was modified, with gradual introduction of lamotrigine (up to 200 mg/day) followed by discontinuation of levetiracetam. In the following months, the patient's condition continued to improve. There was a disappearance of seizures and a progressive recovery of memory function, confirmed by neuropsychological testing.

A repeat CSF assay performed 2 weeks after the second immunomodulatory therapy cycle revealed normal level of both 14-3-3 and total tau proteins. Four months later, brain MRI showed a further reduction of the hyperintense signals in all affected areas. At the most recent visit, 1 year after her initial presentation, the patient has remained seizure-free for 8 months, was oriented, and showed improved memory.