Antibodies to dipeptidyl-peptidase-like protein-6 (DPPX-Ab), a subunit of the Kv4.2
potassium channel, have recently been described in patients with encephalitis.
1
DPPX-Ab are part of an expanding spectrum of autoantibodies to CNS cell surface molecules.
2
–
4
So far, only a few patients with DPPX-Ab have been reported in the literature, and
little is known about treatment responses.
Case report.
A 40-year old woman presented with an unsteady gait, ataxia of the arms, a whole-body
tremor, memory deficits, and panic attacks lasting for 1.5 years. She experienced
a severe weight loss of around 80 kg (previous weight ∼160 kg) and had night sweats
and diarrhea that preceded the neurologic symptoms. Her symptoms led to social withdrawal,
inability to continue her work as a retail saleswoman, and need for help with daily
care. Institutional review board–approved informed consent was obtained to use clinical
and laboratory data in this report.
On admission, the patient was fully oriented and displayed psychomotor slowing and
an impaired short-term memory. She scored 27/30 points on the Mini-Mental State Examination.
More detailed testing revealed deficits in attention, executive functions, figural
memory, and verbal learning, consistent with mild cognitive impairment.
Saccadic pursuit gaze movements were noted in all directions, as were tremors of the
voice, body, and limbs. She displayed a severe acoustic startle response. There was
no paresis; all reflexes were brisk and pyramidal signs were positive. Hypesthesia
was noted in both legs. The patient displayed severe ataxia when sitting or standing.
The maximal walking distance was 500 meters; she walked 200 meters on the 3-minute
walk test (3MWT). The timed up and go test (TUG) took 9.8 seconds.
EEG was normal. Nerve conduction studies displayed a demyelinating sensorimotor polyneuropathy.
Motor evoked potentials of the lower limbs showed prolonged central motor conduction
times for both legs and normal peripheral latencies, consistent with a central lesion
due to the encephalitis. Somatosensory evoked potentials were also impaired, but discrimination
between a peripheral and central lesion was not possible. CSF was normal, with no
evidence of intrathecal immunoglobulin G (IgG) synthesis. S100 protein was elevated
in CSF (3.4 μg/L; normal <2.7 μg/L); tau, phosphorylated tau, and β-amyloid were normal.
Brain MRI was normal initially and 6 months later.
A whole-body CT scan displayed bilateral adrenal masses without significant changes
over 6 months. MRI suggested adrenal adenomas, which were excluded by an endosonographically
guided biopsy. Clinical or laboratory signs of hormone excess were absent. 18F-fluorodeoxyglucose
(FDG)-PET CT showed increased activity in the gastric wall and duodenum. Biopsies
from these regions revealed nonspecific inflammatory changes but no tumor.
Routine workup of blood was normal. A highly positive IgG serum titer of autoantibodies
against DPPX (1/10,000) was noted. Immunostaining demonstrated typical patterns on
DPPX-transfected cells and tissue sections of hippocampus, cerebellum, and primate
myenteric plexus (figure). Tests for other antibodies associated with tumors or autoimmune
inflammatory disorders were negative.
Figure
DPPX antibodies as detected by fluorescence-based immunohistochemistry and a cell-based
assay
Immunohistochemistry displayed binding of the patient's serum immunoglobulin G (IgG)
to rat hippocampus (A), primate myenteric plexus (B), and mouse (C) and primate (D)
cerebellum tissue sections in a staining pattern compatible with dipeptidyl-peptidase-like
protein-6 (DPPX) antibodies. Specificity for DPPX was confirmed in a cell-based assay
by binding of the patient's IgG to HEK293 cells transfected with human DPPX (E) but
not to mock-transfected cells (F). IgG was detected using a fluorescein isothiocyanate–conjugated
antibody from goat (green).
The patient received 1 g IV methylprednisolone per day for 3 days, followed by 80
mg prednisolone orally. At follow-up after 6 weeks, all neurologic symptoms and cognition
had substantially improved, including psychomotor slowing, short-term memory, tremor,
ataxia, reflexes, hypesthesia, pyramidal signs, ocular motor function, and startle
response. After 3 months, all of these symptoms had completely resolved, except a
very slight gait ataxia during the heel-to-toe test with closed eyes. In line with
improved neurologic examination, walking tests showed a maximum distance of 1,500
meters, a 3MWT distance of 260 meters, and a TUG of 7.4 seconds. Nerve conduction
had recovered completely. Repeat CT scans after 3 and 6 months did not show a tumor.
Prednisolone was slowly tapered over 6 months to 5 mg daily as follows: 80 mg/day
for 4 weeks; 1 week each at 70 mg, 60 mg, 50 mg, and 40 mg; 1 month each at 30 mg
and 20 mg; and 2 weeks each at 17.5 mg, 15 mg, 12.5 mg, 10 mg, and 7.5 mg. After 8
weeks of prednisolone treatment (dosed at 40 mg/day), azathioprine was initiated at
50 mg/day. Over 8 weeks, azathioprine was gradually increased to 300 mg/day and achieved
appropriate lymphocyte suppression. Within 6 months, the DPPX-IgG titer markedly declined
to 1/1,000 in serum and 1/320 in CSF. The patient remained clinically stable over
18 months. Her body weight increased to 98 kg over 6 months and remained stable thereafter.
Discussion.
Thus far, 27 cases of autoimmune encephalitis associated with DPPX-Ab have been reported.
In these patients, a clinical phenotype similar to that of our patient was present,
including a prominent startle reflex and neuropsychiatric symptoms.
1,5,6
DPPX has been demonstrated to be expressed in the gastrointestinal tract,
1
suggesting that the patient's diarrhea might be explained by an autoimmune reaction
in the gut. Gastrointestinal symptoms were also present in 13/27 previously reported
patients with DPPX-Ab. Of note, the increased activity in the gastric wall and duodenum
as revealed by 18F-FDG-PET CT scan in our patient might have reflected such underlying
inflammation; this presumption is corroborated by inflammatory changes on gastric
biopsy.
Most patients described so far experienced an initial benefit from glucocorticosteroids
but subsequently relapsed, e.g., during dose tapering. Six of 7 patients required
prolonged immunotherapy including high-dose IVIg, plasma exchange, rituximab, or cyclophosphamide.
Our patient clearly and persistently improved after treatment with prednisolone together
with azathioprine. Such early add-on immunosuppression is well-established in the
treatment of other autoimmune neurologic disorders such as neuromyelitis optica
7
or cerebral vasculitis.
8
In neuromyelitis optica, rituximab has been shown to be very effective. However, this
drug can cause progressive multifocal leukoencephalopathy. In cerebral vasculitis,
treatment is usually initiated with pulsed cyclophosphamide and tapered down to a
milder immunosuppressant such as azathioprine. Cyclophosphamide is a toxic chemotherapy
drug that may cause several side effects, including hematologic malignancies. Therefore,
we suggest that patients with DPPX-Ab–positive encephalitis initially receive immunosuppression
by glucocorticosteroids alone, and if they respond, moderate immunosuppression by
azathioprine be added during tapering of the glucocorticosteroid. A clinical trial
for this disease is highly desirable but difficult to accomplish due to its rarity.