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Letter to the Editor
Chronic autoimmune autonomic ganglionopathy. A rare case of dysautonomia
Ganglionopatía autonómica autoinmune crónica. Una causa rara de disautonomía
J. Idiáquez Cabezasa,
Corresponding author
idiaquez@123.cl

Corresponding author.
, J. Riquelme Alcázarb, M. Calvo Bascuñánc, J.C. Casar Leturiaa
a Departamento de Neurología, Pontificia Universidad Católica de Chile, Santiago, Chile
b Cátedra de Neurología, Universidad de Valparaíso, Reñaca, Viña del Mar, Valparaíso, Chile
c Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Autoimmune autonomic ganglionopathy &#40;AAG&#41; is an acquired immune-mediated disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It was initially described in 1974 as pure pandysautonomia&#44; and considered a variant of Guillain-Barr&#233; syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In 1994&#44; patients with the condition were found to present antibodies specific for the alpha-3 subunit of the ganglionic acetylcholine &#40;ACh&#41; receptor&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Most cases are acute or subacute and occur in the context of recent history of respiratory tract infection&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> We present the case of a patient with slowly progressive dysautonomia and provide data from a small fibre study&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Our patient was a 43-year-old man with no relevant medical history&#46; Approximately a year before the initial assessment&#44; he began to present slowly progressive symptoms of orthostatic intolerance&#44; with dizziness&#44; blurred vision upon standing&#44; and leg weakness when walking&#46; Symptoms improved in the decubitus position&#46; He subsequently began to present frequent syncopes&#46; A cardiological evaluation ruled out heart disease&#44; and the tilt test revealed orthostatic hypotension&#46; The patient underwent an autonomic function study&#46; He reported nocturia&#44; erectile dysfunction&#44; eye and mouth dryness&#44; lack of sweating during exercise&#44; and photophobia&#46; A neurological examination revealed normal cognitive function&#46; The cranial nerve examination showed bilateral fixed mydriasis&#44; normal ocular motility&#44; normal fifth and twelfth cranial nerve function&#44; and normal motor and sensory function&#46; The autonomic function study revealed alterations in cardiac sympathetic&#44; cardiovagal&#44; sudomotor&#44; and pupillary function &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A blood test did not detect anaemia or leukocytosis&#44; and showed normal erythrocyte sedimentation rate and normal levels of glucose&#44; creatinine&#44; vitamin B<span class="elsevierStyleInf">12</span>&#44; and folic acid&#46; The patient tested negative for HIV infection and presented normal levels of serum gamma globulins&#46; An immunity study revealed no anti-Ro&#44; anti-La&#44; or antinuclear antibodies&#46; Imaging studies revealed no signs of tumour&#46; Motor and sensory nerve conduction studies yielded normal results&#46; A skin biopsy revealed normal density of unmyelinated fibres in the epidermis and dermis &#40;sweat glands&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Differential diagnosis of this progressive sympathetic and parasympathetic dysautonomia without sensory or motor involvement included Sj&#246;gren syndrome&#44; which may present as dysautonomia associated with small or large sensory fibre involvement<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#59; our patient did not present antibodies specific for this condition or sensory neuropathy&#46; Amyloidosis may also present in the form of dysautonomia associated with peripheral axonal polyneuropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; our patient did not present heart&#44; kidney&#44; or peripheral nerve involvement&#46; We also considered paraneoplastic dysautonomia&#44; which presents as acute or subacute symptoms of gastrointestinal pseudo-obstruction either in isolation or in association with encephalitis or sensory ganglionopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However&#44; our patient did not present brain or peripheral nerve involvement&#44; and no alterations were found in a chest&#44; abdomen&#44; and prostate examination&#46; Another possible diagnosis was pure autonomic failure &#40;PAF&#41;&#44; which manifests as slowly progressive sympathetic and parasympathetic dysfunction without motor or sensory involvement&#44; secondary to a chronic neurodegenerative process &#40;synucleinopathy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The patient presented bilateral fixed mydriasis secondary to cholinergic denervation of the pupils&#44; a frequent finding in cases of AAG with high antibody titres but rare in patients with PAF&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> which led us to request a study of ganglionic anti-ACh receptor antibodies&#46; The patient tested positive for antibodies against the alpha-3 subunit of the ganglionic ACh receptor&#44; at a concentration above 3&#46;6&#8239;nmol&#47;L &#40;normal level&#44; &#60;0&#46;05&#8239;nmol&#47;L&#59; Southwestern University&#44; TX&#44; USA&#41;&#46; Orthostatic hypotension was treated with midodrine and fludrocortisone&#46; Our patient received immunosuppressive therapy with prednisone and azathioprine&#59; in subsequent months&#44; orthostatic intolerance improved moderately&#44; with occasional episodes of syncope&#46; At a 4-year follow-up consultation&#44; the patient reported no further episodes of syncope and no additional symptoms&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The main manifestations of AAG include orthostatic hypotension&#44; constipation&#44; severe pupillary cholinergic symptoms&#44; urinary symptoms&#44; dry eyes and mouth&#44; and intolerance to heat due to anhidrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Antibodies block ganglionic transmission&#44; causing dysautonomia&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Treatment of acute AAG is based on intravenous immunoglobulins or plasmapheresis&#59; long-term treatment includes prednisone&#44; mycophenolate&#44; azathioprine&#44; and rituximab&#44; in monotherapy or in combination&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> As our patient showed slow symptom progression&#44; we administered prednisone and azathioprine&#44; achieving good results&#46; Patients with symptoms of AAG may test negative for anti&#8211;ACh receptor antibodies and mainly present symptoms of sympathetic dysfunction&#44; with no pupillary symptoms&#44; and respond better to corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In this case&#44; a morphological study revealed preserved innervation of the sweat glands&#44; which supports the hypothesis of impaired transmission without associated neuronal or axonal injury &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; However&#44; prolonged ganglionic transmission blockade may have caused small fibre loss&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Slowly progressive AAG may initially be misdiagnosed as PAF<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#59; immunosuppresive therapy helps identify patients with AAG&#44; who will respond to treatment&#44; unlike those with PAF&#44; a neurodegenerative disease&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Idi&#225;quez Cabezas J&#44; Riquelme Alc&#225;zar J&#44; Calvo Bascu&#241;&#225;n M&#44; Casar Leturia JC&#46; Ganglionopat&#237;a auton&#243;mica autoinmune cr&#243;nica&#46; Una causa rara de disautonom&#237;a&#46; Neurolog&#237;a&#46; 2021&#59;36&#58;388&#8211;390&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Skin biopsy&#46; Left &#40;PGP 9&#46;5 pan-neuronal marker&#41;&#58; normal density of epidermal nerve fibres &#40;10&#46;1 fibres per mm&#44; that is 0&#46;9 standard deviations below the mean for the patient&#8217;s age and sex&#41;&#46; Right &#40;DAPI fluorescent stain&#41;&#58; the arrow points to a normally innervated sebaceous gland&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">DBP&#58; diastolic blood pressure&#59; NE&#58; norepinephrine&#59; SSR&#58; sympathetic skin response&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Test&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normal values<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Cardiac sympathetic function</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Blood pressure &#40;mm Hg&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">122&#47;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Standing</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">80&#47;37&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Blood pressure drop after postural change</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">42&#47;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#60;20&#47;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Plasma NE in decubitus &#40;pg&#47;mL&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">95&#8211;446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Valsalva manoeuvre&#44; phase IV</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Absent&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Isometric exercise</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Baseline DBP &#40;mm Hg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Increase in DBP during exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8805;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Sympathetic sudomotor function</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SSR &#40;&#956;V&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Palms&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Absent&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8805;200&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Soles&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Absent&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8805;100&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Cardiovagal function</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Deep breathing &#40;bpm&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8805;10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Valsalva ratio</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8805;1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>30&#58;15 ratio</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8805;1&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Cholinergic pupillary function</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001&#37; pilocarpine</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pupil diameter after instillation &#40;mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No change&nbsp;\t\t\t\t\t\t\n
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                          "etal" => true
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        "identificador" => "xack533258"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0035" class="elsevierStylePara elsevierViewall">We would like to thank Dr Steven Vernino of University of Texas Southwestern Medical Center for his advice and for the antibody study&#46;</p>"
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