Advertisement
Mayo Clinic Proceedings Home

Unusual Recovery From Acute Panautonomic Neuropathy After Immunoglobulin Therapy

      A 33-year-old woman with acute idiopathic post-ganglionic panautonomic neuropathy experienced prompt recovery of all dysautonomic symptoms after receiving high-dose intravenous immunoglobulin therapy. Her recovery was complete within 6 months after onset of disease. This unusually rapid and complete recovery in comparison with that of historical control subjects suggests that patients with acute, severe, and widespread autonomie failure might benefit from intravenous immunoglobulin therapy.

      Abbreviations:

      APN (acute panautonomic neuropathy), IVIg (intravenous immunoglobulin)
      Panautonomic neuropathy (pandysautonomia) is part of the group of neuropathies characterized by parasympathetic and sympathetic failure with minimal or no somatosensory or motor impairment.
      • Yokota T
      • Hayashi M
      • Hirashima F
      • Mitani M
      • Tanabe H
      • Tsukagoshi H
      Dysautonomia with acute sensory motor neuropathy: a new classification of acute autonomie neuropathy.
      The syndrome is thought to result from an immune-mediated mechanism that can complicate specific disorders (for example, malignant lesions and connective tissue diseases), but the postviral and idiopathic variants are the most common.
      • Hart RG
      • Kanter MC
      Acute autonomie neuropathy: two cases and a clinical review.
      The site of autonomie failure is usually in the efferent postganglionic pathways. Slow, incomplete recovery and persistent orthostatic hypotension are common, and as yet no effective therapy is available.
      • Suarez GA
      • Fealey RD
      • Camilleri M
      • Low PA
      Idiopathic autonomie neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients.
      In the Guillain-Barré syndrome, the immune-mediated somatic counterpart of acute panautonomic neuropathy (APN), intravenous immunoglobulin (IVIg) therapy has been shown to have beneficial effects.
      • van der Meché FGA
      • Schmitz PIM
      • Dutch Guillain-Barré Study Group
      A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome.
      Herein we describe a severely ill patient with APN who recovered after receiving IVIg therapy.

      Report of Case

      A 33-year-old woman had left-sided ptosis, dry mouth, abdominal cramps, and constipation after 6 days of malaise with no fever. After 17 days, she experienced postural dizziness and blurred near vision of the right eye; in addition, she had to compress her lower abdominal area in order to urinate. On the 25th day of illness, she was admitted to our medical center.
      On admission of the patient, supine mercury sphygmo-manometric blood pressure was 110/70 mm Hg. Her heart rate did not change on deep breathing. When she was upright, her blood pressure decreased to 60/30 mm Hg, and she could stand less than 30 seconds. Skin and mucous membranes were dry, and sweating was noted only on the forehead. Both pupils were neither miotic nor dilated but were of a mid-dilatory size, and they were nonreactive. Accommodative power in both eyes was reduced (right, 4 diopter [D]; left, 6 D; normal, greater than 7). The left eye was ptotic, but ptosis disappeared on upward gaze. No sensory or motor disturbances were found.
      Results of routine blood chemistry and hématologie studies were normal. Antinuclear antibodies and sérologie tests for neurotrophic viruses, Borrelia, and syphilis were negative. A cerebrospinal fluid examination and computed tomo-graphic scan of the brain revealed no abnormalities. Findings on electroneurographic motor and sensory conduction studies, late response studies, and computer-assisted heat and cold threshold detection (Triple T, Vickers, Nieuwkoop, The Netherlands) were normal.
      • Jamal GA
      • Hansen S
      • Weir AI
      • Ballantyne JP
      The neurophysiologic investigation of small fiber neuropathies.
      After unexpected noise, forced breathing, and electrical stimulation, sympathetic skin potential responses were reduced in the right hand (0.09 mV; normal, greater than 0.5) and absent in the feet.
      • Soli ven B
      • Maselli R
      • Jaspan J
      • Green A
      • Graziano H
      • Petersen M
      • et al.
      Sympathetic skin response in diabetic neuropathy.
      When the patient was standing and during Valsalva straining, the finger arterial pressure (Finapres, TNO-BioMedical Instrumentation, Amsterdam, The Netherlands) decreased progressively with no increase in heart rate, an indication of impaired vasoconstriction and absent cardio-parasympathetic and cardiosympathetic responses (Fig. 1).
      • Mathias CJ
      • Bannister R
      Investigation of autonomie disorders.
      • Wieling W
      Non-invasive continuous recording of heart rate and blood pressure in the evaluation of neurocardiovascular control.
      During orthostatic hypotensive stress, in which the finger blood pressure decreased from 117/67 mm Hg to 80/47 mm Hg, the baroreceptor-mediated vasopressin release increased adequately from 0.3 ng/L (normal, 0.2 to 1.5) to 3.4 ng/L, an outcome that established integrity of afferent baroreceptor pathways. During the cold pressor test, an abnormally small pressor response was found (systolic/diastolic, 7/5 mm Hg; normal, 10 to 20/10 to 15). While the patient was supine, forearm plasma noradrenaline was extremely low (0.09 nmol/L; normal, 0.86 to 3.40), and adrenaline was normal (0.05 nmol/L; normal, 0.05 to 0.82). During orthostatic hypotensive stress, no increases occurred in adrenaline, and noradrenaline decreased by 0.02 nmol/L. Analysis of these results established that the site of vasomotor failure was in the efferent pathways.
      • Mathias CJ
      • Bannister R
      Investigation of autonomie disorders.
      Figure thumbnail gr1
      Fig. 1Finger arterial blood pressure and heart rate responses in patient with acute panautonomic neuropathy. Note severe, progressive decrease in blood pressure with no change in heart rate when patient was standing (upper left) and during Valsalva straining at 30 mm Hg when she was supine (lower left). Right-hand panels were obtained 5 months after intravenous immunoglobulin treatment. Valsalva ratio increased from 1.0 to 1.6.
      Low-dose bolus injections of intravenous phenylephrine, 12.5 g and 25 g, produced enhanced pressor responses (35/30 mm Hg and 37/25 mm Hg), an indication of denervation supersensitivity. Normally, no pressor response is noted with such doses.
      • Low PA
      Laboratory examination of autonomie failure.
      The pronounced increases in blood pressure induced almost no change in heart rate (from 70 to 68 and from 71 to 69 beats/min, respectively). Intradermal acetylcholine (10 mg) elicited no sweat response orpiloerection. On the basis of these observations, we located the site of vasomotor and sudomotor failure in the postganglionic sympathetic pathways.
      • Low PA
      Laboratory examination of autonomie failure.
      Management with expansion of total body water (daily dietary intake of 200 mmol of sodium chloride, sleeping in a head-up tilt position, and 0.1 mg of fludrocortisone acetate) and performance of physical countermaneuvers
      • van Lieshout JJ
      • ten Harkel AD
      • Wieling W
      Physical manoeuvres for combating orthostatic dizziness in autonomie failure.
      improved orthostatic intolerance, but postural hypotension and the other dysautonomic symptoms remained. Thirty days after the onset of symptoms, a total of 140 g of IVIg therapy (Sandoglobulin, Sandoz Pharma, Switzerland; 1 g/kg of body weight per day for 2 consecutive days) was administered. Five days after the infusion of IVIg, the right pupil reacted slightly to light. Production of saliva and hesitancy of micturition had improved, and constipation had resolved. Syncope or disabling dizziness no longer occurred, but orthostatic hypotension was still severe, and instantaneous heart rate changes were almost absent (supine—blood pressure 132/88 mm Hg and heart rate 68 beats/min; after standing for 1 minute—93/60 mm Hg and 74 beats/min, respectively). During outpatient follow-up, dysautonomic symptoms diminished further. Two months after administration of IVIg therapy, orthostatic hypotension was no longer present (supine, 129/74 mm Hg; after standing for 1 minute, 124/78 mm Hg; and after 5 minutes, 122/78 mm Hg).
      The patient had complete symptomatic recovery within 6 months after onset of disease. Findings on neurologic and electroneurophysiologic examinations were normal except for a reduction in heat discrimination at the ankles (right, 3.4C; left, greater than 10C; normal, less than 2.1C). The sympathetic skin potential responses had returned to normal. On standing and during the Valsalva maneuver, blood pressure and heart rate responses were normal (Fig. 1). The heart rate response to forced breathing of 20/min was normal. While the patient was supine, forearm plasma noradrenaline was slightly reduced (0.78 nmol/L; normal, 0.86 to 3.40), but a normal increase (1.37 nmol/L; normal, 0.71 to 4.14) was found after she had stood 5 minutes. At 1-year follow-up, she was still asymptomatic.

      Discussion

      Our patient had postganglionic idiopathic APN; associated prognosis is poor.
      • Okada F
      • Yamashita I
      • Suwa N
      Two cases of acute pandysautonomia.
      A literature review revealed seven single cases of well-documented postganglionic APN;”
      • Feldman EL
      • Bromberg MB
      • Blaivas M
      • Junck L
      Acute pandysautonomic neuropathy.
      of these, only two patients recovered completely from ortho-static hypotension and other dysautonomic impairments at follow-up of 21 months and 3 years, respectively.
      • Young RR
      • Asbury AK
      • Corbett JL
      • Adams RD
      Pure pan-dysautonomia with recovery: description and discussion of diagnostic criteria.
      • Okada F
      • Yamashita I
      • Suwa N
      Two cases of acute pandysautonomia.
      • Low PA
      • Dyck PJ
      • Lambert EH
      • Brimijoin WS
      • Trautmann JC
      • Malagelada JR
      • et al.
      Acute panautonomic neuropathy.
      • Okada F
      • Shintomi Y
      • Kase M
      Pupillary symptoms in three patients with pandysautonomia.
      • Feldman EL
      • Bromberg MB
      • Blaivas M
      • Junck L
      Acute pandysautonomic neuropathy.
      In three cases, orthostatic hypotension was still present after 2 to 5 years;
      • Okada F
      • Yamashita I
      • Suwa N
      Two cases of acute pandysautonomia.
      • Low PA
      • Dyck PJ
      • Lambert EH
      • Brimijoin WS
      • Trautmann JC
      • Malagelada JR
      • et al.
      Acute panautonomic neuropathy.
      • Okada F
      • Shintomi Y
      • Kase M
      Pupillary symptoms in three patients with pandysautonomia.
      in two cases, follow-up was not documented.
      • Barnett AJ
      • Wagner GR
      Severe orthostatic hypotension: case report and description of response to sympathetico-mimetic drugs.
      • Young RR
      • Asbury AK
      • Corbett JL
      • Adams RD
      Pure pan-dysautonomia with recovery: description and discussion of diagnostic criteria.
      • Okada F
      • Yamashita I
      • Suwa N
      Two cases of acute pandysautonomia.
      • Low PA
      • Dyck PJ
      • Lambert EH
      • Brimijoin WS
      • Trautmann JC
      • Malagelada JR
      • et al.
      Acute panautonomic neuropathy.
      Return of heart rate variability was reported in only one patient.
      • Young RR
      • Asbury AK
      • Corbett JL
      • Adams RD
      Pure pan-dysautonomia with recovery: description and discussion of diagnostic criteria.
      Similarly, in a retrospective study of 27 patients with preganglionic or postganglionic subacute idiopathic autonomie neuropathy, laboratory investigations showed that, a mean of 2 years after the symptoms had begun, severe autonomie failure was present in 63%, ortho-static hypotension in 63%, and reduced heart rate variability in 63%. During a subsequent follow-up of 32 months, the prognosis to recovery remained poor in the entire group.
      • Suarez GA
      • Fealey RD
      • Camilleri M
      • Low PA
      Idiopathic autonomie neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients.
      Although a spontaneous improvement cannot be excluded in our patient, the complete and rapid recovery after IVIg therapy suggests a beneficial effect from IVIg. A recent publication reported a case of APN in which high-dose IVIg therapy was administered during the early stage of disease.
      • Heafield MT
      • Gammage MD
      • Nightingale S
      • Williams AC
      Idiopathic dysautonomia treated with intravenous gamma-globulin.
      Substantial improvement in most autonomie disturbances supported the beneficial effects of IVIg. Because of the poor prognosis of this severely disabling disorder, the absence of effective therapy thus far, and its similarity with the Guillain-Barré syndrome in which IVIg is a recognized therapy, IVIg should be considered in the treatment of patients examined within 1 month after onset of severe, widespread autonomie failure.

      References

        • Yokota T
        • Hayashi M
        • Hirashima F
        • Mitani M
        • Tanabe H
        • Tsukagoshi H
        Dysautonomia with acute sensory motor neuropathy: a new classification of acute autonomie neuropathy.
        ArchNeurol. 1994; 51: 1022-1031
        • Hart RG
        • Kanter MC
        Acute autonomie neuropathy: two cases and a clinical review.
        Arch Intern Med. 1990; 150: 2373-2376
        • Suarez GA
        • Fealey RD
        • Camilleri M
        • Low PA
        Idiopathic autonomie neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients.
        Neurology. 1994; 44: 1675-1682
        • van der Meché FGA
        • Schmitz PIM
        • Dutch Guillain-Barré Study Group
        A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome.
        NEnglJMed. 1992; 326: 1123-1129
        • Jamal GA
        • Hansen S
        • Weir AI
        • Ballantyne JP
        The neurophysiologic investigation of small fiber neuropathies.
        Muscle Nerve. 1987; 10: 537-545
        • Soli ven B
        • Maselli R
        • Jaspan J
        • Green A
        • Graziano H
        • Petersen M
        • et al.
        Sympathetic skin response in diabetic neuropathy.
        Muscle Nerve. 1987; 10: 711-716
        • Mathias CJ
        • Bannister R
        Investigation of autonomie disorders.
        in: Bannister R Mathias CJ Autonomie Failure: A Textbook of Clinical Disorders of the Autonomie Nervous System. 3rd ed. Oxford University Press, Oxford (England)1992: 255-290
        • Wieling W
        Non-invasive continuous recording of heart rate and blood pressure in the evaluation of neurocardiovascular control.
        in: Bannister R Mathias CJ Autonomie Failure: A Textbook of Clinical Disorders of the Autonomie Nervous System. 3rd ed. Oxford University Press, Oxford (England)1992: 291-311
        • Low PA
        Laboratory examination of autonomie failure.
        in: Low PA Clinical Autonomie Disorders: Evaluation and Management. Little, Brown, Boston1993: 169-195
        • van Lieshout JJ
        • ten Harkel AD
        • Wieling W
        Physical manoeuvres for combating orthostatic dizziness in autonomie failure.
        Lancet. 1992; 339: 897-898
        • Barnett AJ
        • Wagner GR
        Severe orthostatic hypotension: case report and description of response to sympathetico-mimetic drugs.
        Am Heart J. 1958; 56: 412-424
        • Young RR
        • Asbury AK
        • Corbett JL
        • Adams RD
        Pure pan-dysautonomia with recovery: description and discussion of diagnostic criteria.
        Brain. 1975; 98: 613-636
        • Okada F
        • Yamashita I
        • Suwa N
        Two cases of acute pandysautonomia.
        ArchNeurol. 1975; 32: 146-151
        • Low PA
        • Dyck PJ
        • Lambert EH
        • Brimijoin WS
        • Trautmann JC
        • Malagelada JR
        • et al.
        Acute panautonomic neuropathy.
        AnnNeurol. 1983; 13: 412-417
        • Okada F
        • Shintomi Y
        • Kase M
        Pupillary symptoms in three patients with pandysautonomia.
        Neuroophthalmology. 1988; 8: 87-93
        • Feldman EL
        • Bromberg MB
        • Blaivas M
        • Junck L
        Acute pandysautonomic neuropathy.
        Neurology. 1991; 41: 746-748
        • Heafield MT
        • Gammage MD
        • Nightingale S
        • Williams AC
        Idiopathic dysautonomia treated with intravenous gamma-globulin.
        Lancet. 1996; 347: 28-29