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Autoimmune autonomic ganglionopathy with late-onset encephalopathy
Autonomic Neuroscience: Basic and Clinical 146 (2009) 29–32
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t n e u
Autoimmune autonomic ganglionopathy with late-onset encephalopathy S.K. Baker a,⁎, C. Morillo b, S. Vernino c a Department of Medicine, Divisions of Physical Medicine & Neurology, Neuromuscular Disease Clinic, McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 b Department of Medicine, Division of Cardiology, Autonomics Laboratory, McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, USA
a r t i c l e
i n f o
Article history: Received 6 August 2008 Received in revised form 10 October 2008 Accepted 20 October 2008 Keywords: Autoimmune autonomic ganglionopathy Nicotinic acetylcholine receptor Encephalopathy IVIg Plasma exchange
a b s t r a c t A 47-year old female presented with a 4 month history of early satiety, constipation, light sensitivity, orthostatic intolerance, siccca, and anhydrosis. Her examination revealed dilated, unreactive pupils with dry eyes and mouth but normal strength, phasic reflexes, and sensation. After 3 min of quiet standing her systolic pressure dropped 70 mmHg with a fixed heart rate of 74 bpm. Her α3 ganglionic AChR level was 2060 pmol/L (normal ≤50). Orthostatic symptoms significantly improved within 10 days of completing 2.0 g/kg IVIg. Her supine norepinephrine (NE) level improved over baseline but remained low (i.e., 0.36 à 0.61 nmol/L). Persisting gut inertia prompted a trial of plasma exchange (PLEx) which restored her supine NE level (2.18 nmol/L), bowel patterns, and pupillary reactivity. Five months later, while her AAG was well controlled, she developed gait unsteadiness, confusion, horizontal and vertical nystagmus, bladder retention, and long tract motor signs. A contrast MRI head was normal. Further serum testing demonstrated binding avidity for neuronal α4 and α7 nAChRs. She responded to highdose steroid and immunomodulation. This is the first case report of AAG presenting with antibodies directed against both peripheral and central nAChRs. It is tempting to speculate that CNS α4 or α7 antibodies may have precipitated the treatmentresponsive encephalopathy. © 2008 Elsevier B.V. All rights reserved.
Autoimmune autonomic ganglionopathy (AAG) is an acquired channelopathy of the peripheral autonomic ganglia. Various designations have been applied to this rare form acquired autonomic failure including autoimmune autonomic neuropathy (Lennon, 2002), idiopathic autonomic neuropathy, (Sandroni et al., 2004) autoimmune autonomic failure (Schroeder et al., 2005), and subacute pandysautonomia (Ramirez et al., 2004). Antibody-mediated blockade of the neuronal nicotinic acetylcholine receptors (nAChR) impairs fast synaptic transmission between the first- and second-order neurons of the sympathetic, parasympathetic, and enteric ganglia (Schroeder et al., 2005; Vernino et al., 2008; Wang et al., 2007). Therefore the current assignment of AAG better reflects the underlying pathology than previous labels. Evidence for the proximal site of autoimmune attack within the autonomic system is borne out of the clinical manifestations which target both arms of the autonomic nervous system. Sympathetic ganglionopathy causes orthostatic hypotension, accompanied by low circulating catecholamine levels, and hypo-/anhydrosis. Attenuation of parasympathetic ganglionic transmission produces sicca, gastrointestinal inertia associated with early satiety and bloating, bladder
atony, impotence, tonic pupils, and blunted cardioacceleration. The pandysautonomia typically evolves subacutely over the course of days to weeks. Resolution may be spontaneous, or slow and incomplete (Vernino et al., 2000) with a monophasic presentation or require immunomodulation/suppression if the disease becomes chronic (Schroeder et al., 2005). While there are a variety of autoimmune encephalitides, and some even associated with peripheral nerve disease (i.e., Isaacs syndrome) (Jarius et al., 2008; Vincent et al., 2004), central nervous system (CNS) involvement in AAG has not been previously described. We report a 47-year-old female with classic subacute AAG who presented with a treatment-responsive late-onset encephalopathy 5 months after the pandysautonomia was successfully controlled with immunomodulation-initially intravenous immune globulin and later plasma exchange. This is the first report of an encephalopathy co-occurring with seropositive AAG. 1. Case report 1.1. Presentation
⁎ Corresponding author. Department of Medicine, Neuromuscular Diseases, Rm 2H22, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905 521 2100x76939. E-mail address: [email protected] (S.K. Baker). 1566-0702/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2008.10.016
Over the course of 3 months a 47-year-old female, first developed dysgeusia prior to becoming aware of xerostomia and xerophthalmia. Recurrent constipation, nausea, vomiting, and early satiety resulted in
30
S.K. Baker et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 29–32
last IVIg) consisting of 3.0 L of plasma removal followed by replacement with 2.5 L of 5% human albumin and 0.5 L of fresh frozen plasma in accordance to a previous report (Schroeder et al., 2005). Of interest, she reported the need for a bowel movement immediately after each PLEx treatment. Indeed, all of her symptoms improved particularly bowel motility, light tolerance, and blood pressure. 1.3. Autonomic studies
Fig. 1. Consecutive tilt-table tests performed at baseline, 2 weeks post-IVIg, and 1 week post-PLEx. At baseline the head-up-tilt lasted for 30 min whereas in subsequent studies it lasted for 10 min. There was a sharp and symptomatic decline in blood pressure at baseline with partial and full correction after IVIg and PLEx, respectively. Note that while the blood pressure gradually declined over time after IVIg, with an antibody level of 0.18 nmol/L, there was no such decline after PLEx when the antibody became undetectable. HR, heart rate (top trace); BP, blood pressure (bottom trace); ⁎, start of head-up tilt; †, end of head-up tilt.
a 15-pound weight loss and prompted multiple emergency department visits. Abdominal plain films revealed several air-fluid levels without obvious distention and a colonoscopy was normal despite a previous diagnosis of ulcerative colitis. She experienced increasing gait unsteadiness due to lightheadedness particularly with postural changes and exertion. An outpatient abdominopelvic CT demonstrated large bowel dilatation with retained fecal matter. Symptomatic progression in addition to urinary hesitancy, reduced sweating, and photosensitivity prompted hospital admission. On examination, she displayed normal cognition. Her mucous membranes were dry and her pupils were dilated and non-reactive to light. There was no ptosis or diplopia. Her muscle stretch reflexes, sensorimotor examination, and gait were normal. She exhibited unsteadiness during a bed-side orthostatic challenge due to a 55 mmHg drop in systolic blood pressure (BP) (i.e., 125 à 70 mmHg) and absent compensatory tachycardia (72 bpm) after 3 min. Bloodwork revealed normal complete blood count, erythrocyte sedimentation rate, C-reactive protein, ferritin, p/c ANCA, ANA, ENA, anti-Hu/Ri/Yo, liver function tests, and serum protein electrophoresis. Her TSH was mildly elevated at 6.7 MU/L. Brain MRI and routine electrodiagnostic studies were normal. She was clinically diagnosed with subacute idiopathic autonomic neuropathy and discharged on L-thyoxine and midodrine (0.1 and 5.0 mg daily, respectively) and encouraged to increase fluid consumption, unrestrict dietary salt, and practice counter-pressure manouvres.
Serial autonomic studies were undertaken at baseline, 2 weeks post-IVIg, and 1 week post-PLEx. Resting supine plasma norepinephrine (NEp) levels were blunted at baseline measuring 0.36 nmol/L. After IVIg the NEp value improved to 0.61 nmol/L but further substantially improved to 2.1 nmol/L post-PLEx. The NEp levels measured after 10 min of head-up-tilt increased by 1.7-fold (1.59 nmol/L) and 4.9-fold (4.55 nmol/L) over baseline (0.92 nmol/L) after IVIg and PLEx, respectively. Tilt-table testing at baseline revealed a fixed heart rate response (74 bpm) over 30 min with a fall in BP from 104/78 mmHg to a mean of 70/48 and a nadir of 53/34 mmHg associated with pre-syncope. Post-IVIg readings were improved as heart rate increased from 65 to 76 bpm over 10 min and BP rose from 104/75 mmHg to a mean of 121/93 and a nadir of 92/56 mmHg. There was an initial overshoot followed by a gradual decline in BP. After PLEx the resting BP had normalized to 125/92 mmHg and was maintained during 10 min of head-up-tilt with a mean value of 133/108 and a nadir of 117/88 mmHg (Fig. 1). 1.4. Pupil-to-iris ratios Eye photos were taken in ambient and lighted conditions to compare pupillomotor function in response to immunomodulation. Pupils were fixed and dilated prior to treatment manifesting a pupil-to-iris ratio of 0.6. IVIg treatment was associated with a reduced ambient pupil-to-iris ratio of 0.5 and partially restored light reactivity causing a 12% drop in the ratio. Antibody removal via PLEx produced further light sensitivity as the pupil-to-iris ratio decreased by 36% (Fig. 2). 1.5. Encephalitis Approximately 2 months after receiving PLEx she developed gait unsteadiness and visual disturbance. On examination there was mild horizontal and vertical nystagmus and slight ataxia. An outpatient MRI head was ordered but before this could be completed her symptoms progressed over 1 week such that she was non-ambulatory due to severe ataxia and more prominent nystagmus. She was disoriented to time and place, confabulatory, and perseveratory. She was not
1.2. Immunomodulation Treatment was initiated with intravenous immunoglobulin (IVIg, 2.0 g/kg over 2 days) with pulse solumedrol (250 mg). Prednisone was started at a dose of 40 mg and midodrine was increased to 2.5 mg five times daily. Two additional single-day IVIg boosters (1.0 g/kg) were administered 4 and 8 weeks after the initial treatment. Despite improved orthostatic symptoms she continued to complain of bowel inertia, light sensitivity, and abnormal taste. A 4-consecutive day trial of plasma exchange (PLEx) was thus undertaken (5 weeks after her
Fig. 2. Pupil-to-iris ratios determined in ambient light and after penlight illumination.
S.K. Baker et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 29–32
dysarthric. Orthostasis was absent and pupils were reactive. She was in urinary retention and had long tract motor signs with positive Babinski reflexes, leg spasticity, and patellar and ankle clonus. An MRI head revealed several scattered T2 hyperintensities in bilateral periventricular and subcortical white matter. Visual evoked potentials (VEPs) demonstrated delays with a mean (±SD) P100 component of 118 ± 6.9 ms and an N120 component of 154.4 ± 12.9 ms. Electroencephalography revealed fluctuating bihemispheric slow waves with no paroxysmal activity. Cerebrospinal fluid analysis revealed a normal protein concentration of 0.39 g/L (normal b0.45 g/L), a mildly elevated IgG of 0.09 g/L (normal 0.01–0.06 g/L), significant pleocytosis with a leukocyte count of 183 per μl (normal b5 per μl), and oligoclonal banding. Serum sodium was 119 mmol/L reflective of SIADH. Pulse solumedrol (500 mg) was administered on 3 consecutive days in addition to IVIg (2.0 g/kg) and later PLEx. Prednisone (80 mg) and azathioprine (150 mg) were added and within 6 weeks she regained normal craniobulbar and motor function. A thorough cancer work-up including a paraneoplastic autoantibody panel (as well as antivoltage-gated potassium channel) was negative. A follow-up MRI brain was normal and repeat VEPs demonstrated normal mean P100 and N120 latencies of 97.4 ± 2.0 and 127.0 ± 5.2 ms, respectively. 1.6. Antibody testing Serum testing for anti-ganglionic nicotinic acetylcholine receptor (nAChR) antibodies were detected by a radioimmunoprecipitation assay employing solubilized 125I-epibatidine-complexed acetylcholine receptors from a human neuroblastoma cell line (IMR-32) (Vernino et al., 2000). The initial antibody level was positive yielding a valueN 40 times the upper limit of normal (2.06 nmol/L, normalb 0.05 nmol/L). After IVIg and prior to PLEx the level dropped to 0.18 nmol/L. Immediately after PLEx the antibodies were undetectable and remained that way during her encephalopathy and 2 months after recovery. However, subsequent additional testing from her first serum sample revealed the presence of antibodies directed against both central α4 and α7 nAChRs (for details on the testing methods, see reference Vernino et al., 2008). 2. Discussion The incidence of subacute pan-autonomic failure is unknown but considered rare. Convincing evidence now suggests that a majority of these patients harbor pathogenic antibodies against ganglionic nAChRs (Lennon et al., 2003; Sandroni et al., 2004; Vernino et al., 2004, 2008, 2000). Detection of high-level antibodies in our patient is consistent with the prominent parasympathetic symptoms of Adie's pupils, intestinal inertia, sicca, urinary hesitancy, and fixed heart rate and confirms the diagnosis of AAG (Sandroni et al., 2004). Initial treatment with IVIg (induction plus 2 monthly boosters) resulted in a significant reduction in antibody level but incomplete remission of orthostatic hypotension and bowel dysmotility. Plasma exchange, by contrast, produced immediate post-treatment derepression of peristalsis – a previously noted phenomenon (Schroeder et al., 2005) – and normalized her plasma norepinephrine levels, cardiovascular response to head-up-tilt, and pupillomotor activity. Given that pupillary dysfunction is an early and specific sign in the diagnosis of experimental AAG return of the pupillary light reflex may serve as a sensitive marker of treatment response (Mukherjee Vernino, 2007). The augmented clinical response corresponded to the elimination of detectable circulating nAChR antibody. Such an observation implies that PLEx may offer superior immunomodulatory effects compared to IVIg when treating patients with AAG. However, a treatment order effect may have favourably biased PLEx as it followed IVIg and permitted longer exposure to prednisone. The generally rapid response to both IVIg and PLEx suggests that the immunologic lesion is a functional rather than destructive ganglionopathy. Indeed, rapid
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symptomatic reversal of autonomic dysfunction mediated by PLEx was recently demonstrated in a 43-year-old man with a 20 year history of AAG (Schroeder et al., 2005). Persisting clinical control with oral prednisone after discontinuation of immunomodulation supports the concept that a combined approach (IVIg or PLEx and immunosuppression) is required to sustain the initial response (Gibbons et al., 2008). Despite adequate control of AAG-related symptoms our patient developed a treatment-responsive encephalopathy which implies an autoimmune etiology (Vernino et al., 2007). Given the detection of antibody binding to both CNS α4 and α7 nAChRs, it is tempting to speculate that these may have precipitated the symptoms of brainstem encephalitis. However, serum testing was performed on her initial sample and we therefore cannot establish that these antibodies were present at the time of her encephalopathy. Interestingly, the presence of α7 nAChR IgG antibodies in 2 of 9 patients with Rasmussen encephalitis has been previously reported (Watson et al., 2005). Antibodies directed against the ionotropic glutamate receptor, GluR3, have also been reported in RE (Rogers et al., 1994) and other focal epilepsies (Pleasure, 2008). Unlike RE our patient did not exhibit focal motor seizures or hemiparesis. Rather altered consciousness, nystagmus, ataxia, bladder retention, and symmetric long tract motor signs characterized her encephalitis. The absence of opthalmoplegia or other cranial neuropathies argues against a diagnosis of Bickerstaff's brainstem encephalitis. Finally, testing for anti-glutamic acid decarboxylase antibodies was negative (Mata et al., 2008) and given the absence of prominent cerebellar involvement or imaging evidence of adnexal pathology mGluR1 (Sillevis Smitt et al., 2000) and NR1/2 (Dalmau et al., 2007) antibodies were not assayed. The α7 nAChR is a homopentameric ligand-gated ion channel predominantly expressed in the cerebral cortex and hippocampus (Seguela et al., 1993). Anti-sense knockdown of α7 nAChRs impairs learning (Curzon et al., 2006) and reduced expression in the temporal cortex has been observed in brains of Alzheimer's disease patients (Yu et al., 2005) suggesting that targeted autoimmunity against these receptors may impair neurocognitive function. Interestingly, the α4 nAChRs are more widely depleted in Alzheimer's brains than the α7 subtype (Court et al., 2001; Nordberg, 2001). Recently, in addition to the current case, 4 non-encephalopathic seropositive AAG patients have been identified to possess antibodies against α7 nAChRs and 2 against α4β2 (Vernino et al., 2008). However, the lack of overt symptoms in patients screened for autoantibodies does not disprove their possible pathogenicity. As this is the first report of α7 nAChR antibody detection in a patient with encephalopathy further clinical observation is required to clarify the role of this novel CNS autoantibody. The clinical significance of the neuronal α4 antibody remains unknown.
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Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t n e u
Autoimmune autonomic ganglionopathy with late-onset encephalopathy S.K. Baker a,⁎, C. Morillo b, S. Vernino c a Department of Medicine, Divisions of Physical Medicine & Neurology, Neuromuscular Disease Clinic, McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 b Department of Medicine, Division of Cardiology, Autonomics Laboratory, McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, USA
a r t i c l e
i n f o
Article history: Received 6 August 2008 Received in revised form 10 October 2008 Accepted 20 October 2008 Keywords: Autoimmune autonomic ganglionopathy Nicotinic acetylcholine receptor Encephalopathy IVIg Plasma exchange
a b s t r a c t A 47-year old female presented with a 4 month history of early satiety, constipation, light sensitivity, orthostatic intolerance, siccca, and anhydrosis. Her examination revealed dilated, unreactive pupils with dry eyes and mouth but normal strength, phasic reflexes, and sensation. After 3 min of quiet standing her systolic pressure dropped 70 mmHg with a fixed heart rate of 74 bpm. Her α3 ganglionic AChR level was 2060 pmol/L (normal ≤50). Orthostatic symptoms significantly improved within 10 days of completing 2.0 g/kg IVIg. Her supine norepinephrine (NE) level improved over baseline but remained low (i.e., 0.36 à 0.61 nmol/L). Persisting gut inertia prompted a trial of plasma exchange (PLEx) which restored her supine NE level (2.18 nmol/L), bowel patterns, and pupillary reactivity. Five months later, while her AAG was well controlled, she developed gait unsteadiness, confusion, horizontal and vertical nystagmus, bladder retention, and long tract motor signs. A contrast MRI head was normal. Further serum testing demonstrated binding avidity for neuronal α4 and α7 nAChRs. She responded to highdose steroid and immunomodulation. This is the first case report of AAG presenting with antibodies directed against both peripheral and central nAChRs. It is tempting to speculate that CNS α4 or α7 antibodies may have precipitated the treatmentresponsive encephalopathy. © 2008 Elsevier B.V. All rights reserved.
Autoimmune autonomic ganglionopathy (AAG) is an acquired channelopathy of the peripheral autonomic ganglia. Various designations have been applied to this rare form acquired autonomic failure including autoimmune autonomic neuropathy (Lennon, 2002), idiopathic autonomic neuropathy, (Sandroni et al., 2004) autoimmune autonomic failure (Schroeder et al., 2005), and subacute pandysautonomia (Ramirez et al., 2004). Antibody-mediated blockade of the neuronal nicotinic acetylcholine receptors (nAChR) impairs fast synaptic transmission between the first- and second-order neurons of the sympathetic, parasympathetic, and enteric ganglia (Schroeder et al., 2005; Vernino et al., 2008; Wang et al., 2007). Therefore the current assignment of AAG better reflects the underlying pathology than previous labels. Evidence for the proximal site of autoimmune attack within the autonomic system is borne out of the clinical manifestations which target both arms of the autonomic nervous system. Sympathetic ganglionopathy causes orthostatic hypotension, accompanied by low circulating catecholamine levels, and hypo-/anhydrosis. Attenuation of parasympathetic ganglionic transmission produces sicca, gastrointestinal inertia associated with early satiety and bloating, bladder
atony, impotence, tonic pupils, and blunted cardioacceleration. The pandysautonomia typically evolves subacutely over the course of days to weeks. Resolution may be spontaneous, or slow and incomplete (Vernino et al., 2000) with a monophasic presentation or require immunomodulation/suppression if the disease becomes chronic (Schroeder et al., 2005). While there are a variety of autoimmune encephalitides, and some even associated with peripheral nerve disease (i.e., Isaacs syndrome) (Jarius et al., 2008; Vincent et al., 2004), central nervous system (CNS) involvement in AAG has not been previously described. We report a 47-year-old female with classic subacute AAG who presented with a treatment-responsive late-onset encephalopathy 5 months after the pandysautonomia was successfully controlled with immunomodulation-initially intravenous immune globulin and later plasma exchange. This is the first report of an encephalopathy co-occurring with seropositive AAG. 1. Case report 1.1. Presentation
⁎ Corresponding author. Department of Medicine, Neuromuscular Diseases, Rm 2H22, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. Tel.: +1 905 521 2100x76939. E-mail address: [email protected] (S.K. Baker). 1566-0702/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2008.10.016
Over the course of 3 months a 47-year-old female, first developed dysgeusia prior to becoming aware of xerostomia and xerophthalmia. Recurrent constipation, nausea, vomiting, and early satiety resulted in
30
S.K. Baker et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 29–32
last IVIg) consisting of 3.0 L of plasma removal followed by replacement with 2.5 L of 5% human albumin and 0.5 L of fresh frozen plasma in accordance to a previous report (Schroeder et al., 2005). Of interest, she reported the need for a bowel movement immediately after each PLEx treatment. Indeed, all of her symptoms improved particularly bowel motility, light tolerance, and blood pressure. 1.3. Autonomic studies
Fig. 1. Consecutive tilt-table tests performed at baseline, 2 weeks post-IVIg, and 1 week post-PLEx. At baseline the head-up-tilt lasted for 30 min whereas in subsequent studies it lasted for 10 min. There was a sharp and symptomatic decline in blood pressure at baseline with partial and full correction after IVIg and PLEx, respectively. Note that while the blood pressure gradually declined over time after IVIg, with an antibody level of 0.18 nmol/L, there was no such decline after PLEx when the antibody became undetectable. HR, heart rate (top trace); BP, blood pressure (bottom trace); ⁎, start of head-up tilt; †, end of head-up tilt.
a 15-pound weight loss and prompted multiple emergency department visits. Abdominal plain films revealed several air-fluid levels without obvious distention and a colonoscopy was normal despite a previous diagnosis of ulcerative colitis. She experienced increasing gait unsteadiness due to lightheadedness particularly with postural changes and exertion. An outpatient abdominopelvic CT demonstrated large bowel dilatation with retained fecal matter. Symptomatic progression in addition to urinary hesitancy, reduced sweating, and photosensitivity prompted hospital admission. On examination, she displayed normal cognition. Her mucous membranes were dry and her pupils were dilated and non-reactive to light. There was no ptosis or diplopia. Her muscle stretch reflexes, sensorimotor examination, and gait were normal. She exhibited unsteadiness during a bed-side orthostatic challenge due to a 55 mmHg drop in systolic blood pressure (BP) (i.e., 125 à 70 mmHg) and absent compensatory tachycardia (72 bpm) after 3 min. Bloodwork revealed normal complete blood count, erythrocyte sedimentation rate, C-reactive protein, ferritin, p/c ANCA, ANA, ENA, anti-Hu/Ri/Yo, liver function tests, and serum protein electrophoresis. Her TSH was mildly elevated at 6.7 MU/L. Brain MRI and routine electrodiagnostic studies were normal. She was clinically diagnosed with subacute idiopathic autonomic neuropathy and discharged on L-thyoxine and midodrine (0.1 and 5.0 mg daily, respectively) and encouraged to increase fluid consumption, unrestrict dietary salt, and practice counter-pressure manouvres.
Serial autonomic studies were undertaken at baseline, 2 weeks post-IVIg, and 1 week post-PLEx. Resting supine plasma norepinephrine (NEp) levels were blunted at baseline measuring 0.36 nmol/L. After IVIg the NEp value improved to 0.61 nmol/L but further substantially improved to 2.1 nmol/L post-PLEx. The NEp levels measured after 10 min of head-up-tilt increased by 1.7-fold (1.59 nmol/L) and 4.9-fold (4.55 nmol/L) over baseline (0.92 nmol/L) after IVIg and PLEx, respectively. Tilt-table testing at baseline revealed a fixed heart rate response (74 bpm) over 30 min with a fall in BP from 104/78 mmHg to a mean of 70/48 and a nadir of 53/34 mmHg associated with pre-syncope. Post-IVIg readings were improved as heart rate increased from 65 to 76 bpm over 10 min and BP rose from 104/75 mmHg to a mean of 121/93 and a nadir of 92/56 mmHg. There was an initial overshoot followed by a gradual decline in BP. After PLEx the resting BP had normalized to 125/92 mmHg and was maintained during 10 min of head-up-tilt with a mean value of 133/108 and a nadir of 117/88 mmHg (Fig. 1). 1.4. Pupil-to-iris ratios Eye photos were taken in ambient and lighted conditions to compare pupillomotor function in response to immunomodulation. Pupils were fixed and dilated prior to treatment manifesting a pupil-to-iris ratio of 0.6. IVIg treatment was associated with a reduced ambient pupil-to-iris ratio of 0.5 and partially restored light reactivity causing a 12% drop in the ratio. Antibody removal via PLEx produced further light sensitivity as the pupil-to-iris ratio decreased by 36% (Fig. 2). 1.5. Encephalitis Approximately 2 months after receiving PLEx she developed gait unsteadiness and visual disturbance. On examination there was mild horizontal and vertical nystagmus and slight ataxia. An outpatient MRI head was ordered but before this could be completed her symptoms progressed over 1 week such that she was non-ambulatory due to severe ataxia and more prominent nystagmus. She was disoriented to time and place, confabulatory, and perseveratory. She was not
1.2. Immunomodulation Treatment was initiated with intravenous immunoglobulin (IVIg, 2.0 g/kg over 2 days) with pulse solumedrol (250 mg). Prednisone was started at a dose of 40 mg and midodrine was increased to 2.5 mg five times daily. Two additional single-day IVIg boosters (1.0 g/kg) were administered 4 and 8 weeks after the initial treatment. Despite improved orthostatic symptoms she continued to complain of bowel inertia, light sensitivity, and abnormal taste. A 4-consecutive day trial of plasma exchange (PLEx) was thus undertaken (5 weeks after her
Fig. 2. Pupil-to-iris ratios determined in ambient light and after penlight illumination.
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dysarthric. Orthostasis was absent and pupils were reactive. She was in urinary retention and had long tract motor signs with positive Babinski reflexes, leg spasticity, and patellar and ankle clonus. An MRI head revealed several scattered T2 hyperintensities in bilateral periventricular and subcortical white matter. Visual evoked potentials (VEPs) demonstrated delays with a mean (±SD) P100 component of 118 ± 6.9 ms and an N120 component of 154.4 ± 12.9 ms. Electroencephalography revealed fluctuating bihemispheric slow waves with no paroxysmal activity. Cerebrospinal fluid analysis revealed a normal protein concentration of 0.39 g/L (normal b0.45 g/L), a mildly elevated IgG of 0.09 g/L (normal 0.01–0.06 g/L), significant pleocytosis with a leukocyte count of 183 per μl (normal b5 per μl), and oligoclonal banding. Serum sodium was 119 mmol/L reflective of SIADH. Pulse solumedrol (500 mg) was administered on 3 consecutive days in addition to IVIg (2.0 g/kg) and later PLEx. Prednisone (80 mg) and azathioprine (150 mg) were added and within 6 weeks she regained normal craniobulbar and motor function. A thorough cancer work-up including a paraneoplastic autoantibody panel (as well as antivoltage-gated potassium channel) was negative. A follow-up MRI brain was normal and repeat VEPs demonstrated normal mean P100 and N120 latencies of 97.4 ± 2.0 and 127.0 ± 5.2 ms, respectively. 1.6. Antibody testing Serum testing for anti-ganglionic nicotinic acetylcholine receptor (nAChR) antibodies were detected by a radioimmunoprecipitation assay employing solubilized 125I-epibatidine-complexed acetylcholine receptors from a human neuroblastoma cell line (IMR-32) (Vernino et al., 2000). The initial antibody level was positive yielding a valueN 40 times the upper limit of normal (2.06 nmol/L, normalb 0.05 nmol/L). After IVIg and prior to PLEx the level dropped to 0.18 nmol/L. Immediately after PLEx the antibodies were undetectable and remained that way during her encephalopathy and 2 months after recovery. However, subsequent additional testing from her first serum sample revealed the presence of antibodies directed against both central α4 and α7 nAChRs (for details on the testing methods, see reference Vernino et al., 2008). 2. Discussion The incidence of subacute pan-autonomic failure is unknown but considered rare. Convincing evidence now suggests that a majority of these patients harbor pathogenic antibodies against ganglionic nAChRs (Lennon et al., 2003; Sandroni et al., 2004; Vernino et al., 2004, 2008, 2000). Detection of high-level antibodies in our patient is consistent with the prominent parasympathetic symptoms of Adie's pupils, intestinal inertia, sicca, urinary hesitancy, and fixed heart rate and confirms the diagnosis of AAG (Sandroni et al., 2004). Initial treatment with IVIg (induction plus 2 monthly boosters) resulted in a significant reduction in antibody level but incomplete remission of orthostatic hypotension and bowel dysmotility. Plasma exchange, by contrast, produced immediate post-treatment derepression of peristalsis – a previously noted phenomenon (Schroeder et al., 2005) – and normalized her plasma norepinephrine levels, cardiovascular response to head-up-tilt, and pupillomotor activity. Given that pupillary dysfunction is an early and specific sign in the diagnosis of experimental AAG return of the pupillary light reflex may serve as a sensitive marker of treatment response (Mukherjee Vernino, 2007). The augmented clinical response corresponded to the elimination of detectable circulating nAChR antibody. Such an observation implies that PLEx may offer superior immunomodulatory effects compared to IVIg when treating patients with AAG. However, a treatment order effect may have favourably biased PLEx as it followed IVIg and permitted longer exposure to prednisone. The generally rapid response to both IVIg and PLEx suggests that the immunologic lesion is a functional rather than destructive ganglionopathy. Indeed, rapid
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symptomatic reversal of autonomic dysfunction mediated by PLEx was recently demonstrated in a 43-year-old man with a 20 year history of AAG (Schroeder et al., 2005). Persisting clinical control with oral prednisone after discontinuation of immunomodulation supports the concept that a combined approach (IVIg or PLEx and immunosuppression) is required to sustain the initial response (Gibbons et al., 2008). Despite adequate control of AAG-related symptoms our patient developed a treatment-responsive encephalopathy which implies an autoimmune etiology (Vernino et al., 2007). Given the detection of antibody binding to both CNS α4 and α7 nAChRs, it is tempting to speculate that these may have precipitated the symptoms of brainstem encephalitis. However, serum testing was performed on her initial sample and we therefore cannot establish that these antibodies were present at the time of her encephalopathy. Interestingly, the presence of α7 nAChR IgG antibodies in 2 of 9 patients with Rasmussen encephalitis has been previously reported (Watson et al., 2005). Antibodies directed against the ionotropic glutamate receptor, GluR3, have also been reported in RE (Rogers et al., 1994) and other focal epilepsies (Pleasure, 2008). Unlike RE our patient did not exhibit focal motor seizures or hemiparesis. Rather altered consciousness, nystagmus, ataxia, bladder retention, and symmetric long tract motor signs characterized her encephalitis. The absence of opthalmoplegia or other cranial neuropathies argues against a diagnosis of Bickerstaff's brainstem encephalitis. Finally, testing for anti-glutamic acid decarboxylase antibodies was negative (Mata et al., 2008) and given the absence of prominent cerebellar involvement or imaging evidence of adnexal pathology mGluR1 (Sillevis Smitt et al., 2000) and NR1/2 (Dalmau et al., 2007) antibodies were not assayed. The α7 nAChR is a homopentameric ligand-gated ion channel predominantly expressed in the cerebral cortex and hippocampus (Seguela et al., 1993). Anti-sense knockdown of α7 nAChRs impairs learning (Curzon et al., 2006) and reduced expression in the temporal cortex has been observed in brains of Alzheimer's disease patients (Yu et al., 2005) suggesting that targeted autoimmunity against these receptors may impair neurocognitive function. Interestingly, the α4 nAChRs are more widely depleted in Alzheimer's brains than the α7 subtype (Court et al., 2001; Nordberg, 2001). Recently, in addition to the current case, 4 non-encephalopathic seropositive AAG patients have been identified to possess antibodies against α7 nAChRs and 2 against α4β2 (Vernino et al., 2008). However, the lack of overt symptoms in patients screened for autoantibodies does not disprove their possible pathogenicity. As this is the first report of α7 nAChR antibody detection in a patient with encephalopathy further clinical observation is required to clarify the role of this novel CNS autoantibody. The clinical significance of the neuronal α4 antibody remains unknown.
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