Confabulation, amnesia and motor memory loss as a presentation of apparent ITPR1 antibody autoimmune encephalitis

Abstract

A 59-year-old woman presented to the hospital with acute, hypoactive altered mental status. Her symptoms had begun 3 days prior when she developed hallucinations, urinary and faecal incontinence, and somnolence. She also exhibited confabulations, amnesia, motor memory loss and a wide-based gait. Medical, psychiatric and neurological evaluations including imaging and laboratory workup were unrevealing. Treatment for possible Wernicke encephalopathy and psychosis with high-dose intravenous thiamine and antipsychotic medications did not lead to improvement. After discharge, a send-out cerebrospinal fluid autoimmune encephalitis panel resulted positive for the newly identified neuronal inositol triphosphate receptor one (ITPR1) antibody. This prompted readmission for intravenous steroids, plasmapheresis and intravenous immunoglobulin, which yielded mild clinical improvement. Here, we describe confabulations and psychiatric symptoms as novel manifestations of the primary presentation of anti-ITPR1 encephalitis in an effort to promote faster recognition of this disease and early initiation of treatment in suspected cases.

Background

Autoimmune encephalitis encompasses a group of conditions in which the immune system attacks the healthy tissue of the central nervous system (CNS). There are multiple autoimmune encephalitis diseases, including antibodies to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid B (GABAB), glutamate decarboxylase (GAD), Hu and leucine-rich glioma-inactivated 1 (LGI-1) receptors that primarily present with neurological or neuropsychiatric syndromes.^{1 2} The neuronal inositol triphosphate receptor one (ITPR1) antibody is a newly discovered autoantibody that has been reported in at least 17 patients to date.³ Patients with ITPR1 autoantibody have been noted to have a broad range of neurological symptoms, including cerebellar ataxia, nystagmus, peripheral neuropathy and seizures.³ In addition, ITPR1 autoantibody has an association with malignancy. Of the 14 patients found to have ITPR1 autoimmune encephalitis, 5 were found to have one or more cancers.³

While neurological abnormalities are commonly reported in association with autoimmune encephalitis, psychiatric manifestations, including hallucinations, delusions, short-term memory loss, psychosis and mania, have also been reported, including in NMDA receptor encephalitis.⁴ Confabulation as a presentation of autoimmune encephalitis has been rarely described and has not previously been reported in association with ITPR1 autoimmune encephalitis.⁵

Case presentation

A 59-year-old fully functional woman, with a history of hypertension, presented to the hospital with acute encephalopathy. Per her husband, she had been mildly withdrawn for about 12 months following the deaths of two of her siblings. Over the 3 days prior to admission, she developed hallucinations, urinary and faecal incontinence, and complete unresponsiveness to verbal stimuli. Two days into her hospital course, after fluid resuscitation, she became more alert; however, she remained oriented only to self despite frequent reorientation. Subsequent neurological examinations elicited wide and tremulous gait that prohibited her from standing independently, severely impaired motor memory, visual hallucinations and profound confabulations when confronted with her retrograde and anterograde amnesia. Her wide-based gait and difficulty following commands limited assessment of her lower extremity coordination and ataxia; however, her reflexes, sensation, strength, cranial nerves and upper extremity coordination were normal. Although she was hospitalised for several weeks, no aetiology of her clinical presentation was identified, and she had no improvement in her symptoms. As she was clinically stable, she was discharged to subacute rehabilitation.

Investigations

Initial laboratory tests, including blood and urine cultures, drug screen, metabolic panel and complete blood count, were only notable for mild hypokalaemia. The patient was started on high-dose intravenous thiamine, anticoagulation for an incidentally found pulmonary embolism, intravenous fluids and potassium repletion. Extensive laboratory tests, including cerebrospinal fluid (CSF) studies and rheumatological markers, did not elicit any clues towards her diagnosis (table 1). Brain MRI, whole-body CT scans and electroencephalogram also did not identify any abnormalities, including primary neoplastic or paraneoplastic processes, that could have explained the patient’s presentation. While thiamine was given prior to laboratory evaluation, MRI findings and neurological evaluation were not consistent with Wernicke encephalopathy. A sample of her spinal fluid was sent to an outside hospital for an autoimmune encephalitis panel. The initial results were negative (table 2).

Table 1.

Metabolic, infectious, neurological and malignant workup were negative

Lab test	Result (range)	Lab test	Result
WBC	14 (7.3–15.4)	TSH	6.226 (0.34–5.6)
Hgb	16.8 (16.8–11.6)	T3	48.6 (87–178)
Platelet	432 (255–403)	T4	0.92 (0.58–1.64)
Na+	137 (137–142)	Thyroid peroxidase Ab	2 (<9)
K+	3.7 (2.6–4.0)	Viral screen	Negative
Ca2+	9.4 (6.8–9.4)	Blood culture	Negative
Mg2+	2.7 (1.7–2.7)	CSF cell Count	2 (0)
Phosphate	2.4 (2.4–3.6)	CSF protein	54 (15–45)
Cl	98 (98–112)	CSF cultures	Negative
Cr	0.8 (0.5–1.0)	CSF viral panel	Negative
BUN	22 (3–22)	CSF tube 1	W1, R76
CO2	21 (20–27)	CSF tube 4	W0, R3
CK	60 (38–234)	ds-DNA Ab	Negative
ESR	90 (2–39)	ANA	Negative
CRP	49.9 (0.2–5.0)	Ammonia	68 (11–35)
Troponin	<0.03	AST	58 (23–58)
Drug screen	Negative	ALT	37 (25–46)

ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; CRP, C reactive protein; CSF, cerebrospinal fluid; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; TSH, thyroid-stimulating hormone; WBC, white blood cells.

Table 2.

Autoimmune encephalitis panel noted to be negative

Antibody (CSF)	Result	Unit	Reference value	Test type
AMPA-R Ab	Negative		Negative	IF
Amphiphysin Ab	Negative	Titre	<1:2	IF
AGNA-1	Negative	Titre	<1:2	Immunoblot
ANNA-1	Negative	Titre	<1:2	Immunoblot
ANNA-2	Negative	Titre	<1:2	Immunoblot
ANNA-3	Negative	Titre	<1:2	Immunoblot
CASPR2-IgG CBA	Negative		Negative	Live-cell assay (IF, immunoblot)
CRMP-5-IgG	Negative	Titre	<1:2	Western blot
DPPX Ab IFA	Negative		Negative	Cell-binding assay, IF
GABA-B-R Ab CBA	Negative		Negative	Cell-binding assay
GAD65 Ab Assay	0.00	nmol/L	<−0.02	Cell-binding assay
GFAP	Negative		Negative	IF
LGI1-IgG CBA	Negative		Negative	Cell-binding assay
mGlur1 Ab IFA	Negative		Negative	Cell-binding assay, immunofluorescence
NMDA-R Ab CBA	Negative		Negative	Cell-binding assay, IF titre
PCA-Tr	Negative	Titre	Negative	Immunoblot
PCA-1	Negative	Titre	<1:2	Immunoblot
PCA-2	Negative	Titre	<1:2	Immunoblot

CSF, cerebrospinal fluid; IF, immunofluorescence.

Differential diagnosis

The initial differential diagnosis included psychiatric disorders such as psychosis, post-traumatic stress disorder, dissociative amnesia and Wernicke-Korsakoff syndrome, as well as neurological disorders such as subclinical seizures, brain malignancy and encephalitis. Other possibilities included medication or drug-induced encephalitis, toxic-metabolic encephalopathies, paraneoplastic syndromes or infections including meningitis.

Treatment

Two weeks after discharge, the outside hospital ran our CSF sample for ITPR1 autoantibody for research purposes using transfected cell-based assay (serum, 1:10; CSF, 1:2), which returned positive for ITPR1-specific IgG. The patient was readmitted to the hospital for urgent initiation of immunotherapy. She did not show improvement with intravenous methylprednisolone and was started on plasmapheresis followed by intravenous immunoglobulins. Despite minimal to no improvements reported in case reports of treated ITPR1, our patient had some improvement in encephalopathy following treatment, including improved mobility and mentation. However, she continued to be intermittently oriented with impaired memory. Following discussion with our neurology colleagues, it was felt that potential improvement could continue to occur in the 2 weeks following treatment. She was discharged with a steroid taper, mycophenolate mofetil and close neurological follow-up.

Outcome and follow-up

Following discharge, the patient completed her prolonged steroid taper and remained on maintenance mycophenolate mofetil. After a year of nursing home care, she was able to move back home to live with her spouse. With a long course of physical therapy and continued home exercises, she has shown improved mobility, including independent ambulation, improved mentation and no new neurological symptoms or deterioration. She continues to follow with neurology for this presumed case of ITPR1 encephalitis.

Discussion

ITPR1 autoimmune encephalitis is part of an increasing number of identified causes of autoimmune encephalitis. Its variable presentation, imaging and laboratory abnormalities present diagnostic challenges. In particular, review of the literature shows that patients with ITPR1 autoimmune encephalitis have a variety of findings on MRI, including normal results, brain atrophy or enhanced T2 signalling. This variety of findings also extends to CSF studies.³ Thus, unexplained neurological and primary psychiatric symptoms, including confabulations, should prompt early consideration of autoimmune encephalitis, including the newly identified ITPR1 subset. CSF testing for these autoimmune antibodies is only performed in certain laboratories. Awaiting these test results can lead to significant delays in diagnosis and treatment, an issue of clinical significance as delays in treatment initiation portend worse prognoses.^{2 6} Furthermore, this case highlights the importance of remembering that not all autoantibodies associated with autoimmune encephalitis have been described in the literature or are routinely tested. Due to the lengthy turnaround time of CSF autoimmune testing, Graus et al suggest that it is unrealistic to include a positive antibody test in the diagnostic criteria for autoimmune encephalitis. Factors such as subacute onset of new CNS findings, unexplained seizures, CSF pleocytosis, MRI with normal or non-specific abnormalities, and exclusion of other causative diseases should prompt consideration of autoimmune encephalitis and early initiation of treatment.² Our patient’s subtle subacute neurological findings of wide-based gait and impaired motor memory, along with normal MRI findings and exclusion of other possible aetiologies led us to assess for autoimmune encephalitis, but treatment was not initiated until the presumed causative antibody was identified.

It is important to acknowledge several limitations to this study. First, a serum panel for autoimmune antibodies was never sent as it was not recommended at the time. It is known that individuals with autoimmune encephalitis have had positive autoantibodies in serum and not in CSF.⁷ As such, it is possible that our patient may have had concomitant autoantibodies. Second, the ITPR1 antibody was discovered when the outside hospital ran a research study on old CSF samples. A retest was never completed following discussion with the patient and our neurology colleagues as it was felt that it would be better to initiate treatment. This echoes the first point that our patient may have had other unidentified autoantibodies present. Despite these limitations, it is important to recognise that confabulation as a primary symptom is exceedingly rare in autoimmune encephalitis regardless of which autoantibody is identified.

When therapy is warranted, it is important to remember that the mainstay of treatment is immunosuppression, and this may complicate the diagnosis of certain malignancies such as lymphoma or lead to adverse events. This is especially important given the strong paraneoplastic associations with autoimmune encephalitis.^{8 9} Consistent with this case, it is prudent to complete a thorough evaluation for underlying malignancy concurrently with an encephalitis workup. In light of these considerations, earlier recognition of the broad presentation of ITPR1 autoimmune encephalitis and that of other autoimmune encephalopathies, including unexplained confabulations, loss of motor memory and amnesia, should prompt early initiation of treatment with hopes of yielding better clinical outcomes.

Learning points.

• The newly discovered neuronal inositol triphosphate receptor one (ITPR1) autoantibody causes an autoimmune encephalitis that presents with a broad range of neurological and psychiatric symptoms, including confabulations. This antibody notably has an association with malignancy.

• Psychiatric symptoms are commonly present in autoimmune encephalopathies; however, confabulation as the primary presentation of disease has only been seen in rare cases in the literature. To our knowledge, it has never been reported in ITPR1 encephalitis.

• The diverse clinical presentation, prolonged turnaround time for antibody testing and remaining unknown causes of autoimmune encephalitis underscore the need for diagnostic criteria that promote early consideration of this disease. Once alternative causes have been excluded, we urge clinicians to think about autoimmune encephalitis in patients with new central nervous system findings, unexplained seizures, cerebrospinal fluid pleocytosis and brain MRI with either non-specific or no abnormalities.

• Given the significant disability and mortality associated with most autoimmune encephalitis, earlier recognition of these syndromes, including the ITPR1 autoantibody subset, would promote more rapid testing and shorter duration to therapeutic intervention, thereby yielding improved patient outcomes. Heightened awareness of these diseases may also identify areas requiring further research.

Ethics statements

Patient consent for publication

Next of kin consent obtained.