Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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The syndrome of acute pandysautonomia is characterized by acute onset (onset to peak symptoms within 1 month) of severe and disabling autonomic failure affecting sympathetic, parasympathetic, and enteric functions. If initial symptoms are episodic (syncope) the onset may not be as precise, and, for the purpose of this article, subacute (1 to 2 months) presentations are also included. There may be an inciting event that accounts for unrestrained immune activation, such as an acute infection, vaccination, surgery, or an occult cancer. Acute metabolic disorders and toxic exposures can also cause similar manifestations. The clinical features consist of variable involvement of sympathetic, parasympathetic, and enteric portions of the autonomic nervous system. Other portions of the nervous system may be involved less frequently: brain, somatic sensory, and rarer motor nerve fibers. Symptomatic treatment is complex and is helpful in supporting function. If an autoimmune etiology is identified, immunomodulatory treatments should be employed early in the course to avoid progressive disability. In this article, the author discusses various clinical presentations, with emphasis on early diagnosis, current pathophysiology, and treatment.
Immune-mediated autonomic disorders:
(1) Systemic autoimmune disorders with peripheral autonomic neuropathic manifestations: primary Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis
(2) Autoimmune autonomic ganglionopathy with positive or negative serum ganglionic (neuronal) acetylcholine receptor antibodies
(3) Primary autonomic neuropathies:
A. Acute sensory and autonomic neuropathy, idiopathic (ASAN)
B. Acute sensory and autonomic neuronopathy (ASANN)
C. Acute autonomic sensory motor neuropathy (AASMN) (variant of Guillain Barre syndrome)
D. Idiopathic gastrointestinal dysmotility
E. Idiopathic anhidrosis
(4) Paraneoplastic autonomic neuropathies: anti-Hu (ANNA-1) and anti-CRMP5 (CV2)
(5) Autoimmune neuromuscular disorders with autonomic manifestations: Lambert-Eaton myasthenic syndrome, disorders with positive LGI1 or CASPR2 antibodies, Guillain-Barré syndrome
(6) Iatrogenic autonomic neuropathies: chemotherapeutic agents, checkpoint inhibitors
• Acute pandysautonomia is characterized by autonomic failure affecting sympathetic, parasympathetic, and enteric functions.
• In some cases, the autoimmune etiology is supported by the presence of antibodies against neuronal antigens.
• Immunomodulating treatments should be employed early in the course to avoid progressive disability.
The syndrome of acute pandysautonomia was first reported in the neurologic literature by Young and colleagues in 1969 and was later discussed in more detail in the same patient as "pure pandysautonomia with recovery" (64). The patient showed "severe postural hypotension without change in heart rate, leading occasionally to fainting without change in heart rate, total absence of sweating, extreme dryness of eyes, nasal and oral mucous membranes, midposition nonreactive pupils, absence of bowel sounds and a hypotonic weak bladder." Appenzeller and Kornfeld first coined the term "acute pandysautonomia" (02), and similar cases were also reported later as acute autonomic neuropathy, acute panautonomic neuropathy, acute idiopathic pandysautonomia, and idiopathic autonomic neuropathy (30; 47).
A more heterogeneous picture of the syndrome emerged over the years with reports of variable recovery and associated sensory or sensorimotor symptoms (02; 30; 22; 49). A subgroup of patients with pure cholinergic dysautonomia has been described, and variable involvement of central nervous system sites may be present (45). Some cases may have limited autonomic neuropathic features to include postural orthostatic tachycardia syndrome (POTS) (42). The clinical presentation of acute pandysautonomia is a useful clinical syndromic concept leading to specific work up and treatment. Careful evaluation of other targeted segments of the nervous system is frequently needed ranging from encephalitis to acute autonomic and sensory or sensorimotor neuropathy to Guillain-Barre syndrome with dysautonomia (30; 22; 49). Toxic immune and metabolic etiologies like treatment induced diabetic autonomic neuropathy should be considered (63; 46; 32; 33). The presence of ganglionic acetylcholine receptor antibodies (gAChR) or other paraneoplastic antibodies in patients’ sera and the development of an experimental animal model of acute pandysautonomia have led to the concept of autoimmune autonomic ganglionopathy (27; 58; 21; 33).
• Acute pandysautonomia refers to acute development, which occurs over a period of days or weeks and is usually monophasic, of moderate to severe sympathetic, parasympathetic, and enteric autonomic dysfunction.
• Brain, somatic motor, and sensory functions may be involved.
Symptoms. A prodrome of febrile or viral illness may precede the onset of symptoms in 50% of cases (30; 47; 41). The symptoms evolve over a period of a few days or weeks, but may be more gradual, and patients with a chronic course are also being recognized (02; 64; 47; 27; 41; 29; 34; 38). Initial nonspecific symptoms of lethargy and fatigue are followed by autonomic symptoms: orthostatic lightheadedness and orthostatic hypotension leading to vasovagal syncope, blurring of vision, abdominal distension, pain, and dryness of eyes, voiding difficulty with or without nocturia or urinary retention (40), and various degrees of anhidrosis may coexist. The most common symptoms at onset are related to orthostatic intolerance, and gastrointestinal and sudomotor dysfunction (47; 27). At the peak of illness all autonomic functions are affected in various degrees. Orthostatic symptoms and syncope (70% of patients), blurred near vision, urinary retention or incontinence, abdominal colic, distention, and at times ileus (70% of patients) are the most disabling symptoms (64). A phase of autonomic hyperactivity with profuse sweating, excessive lacrimation, salivation, and episodic piloerection may precede the loss of function. Extra nonautonomic manifestations continue to be reported, particularly from Asia (37). Pain in the region of the parotid and submaxillary salivary glands, intermittent pain in the region of the vulva, and paroxysmal coughing are occasionally reported. Significant weight loss may occur consequent to malnutrition and diarrhea. Paresthesias, cognitive/psychiatric symptoms, and endocrine abnormalities have also been described (37).
Examination findings. The physical examination findings are complemented by autonomic reflex testing and organ-specific function testing abnormalities. Neurogenic orthostatic hypotension with a fixed heart rate points to sympathetic and parasympathetic cardiac involvement. It is often profound (12) and associated with lightheadedness or loss of consciousness. Pupils are midposition, dilated or unequal, and unreactive to bright light and accommodation or may have premature pupillary redilation despite persistent light stimulation, termed “pupillary fatigue” (17). There may be unilateral or bilateral ptosis. Dry and peeling skin, keratitis sicca, a distended abdomen, absent bowel sounds, a distended urinary bladder, diminished rectal tone, atonic dartos muscle, and absent bulbocavernous reflex may be observed. In a typical case, mental, motor, and sensory functions are intact, but mild sensory disturbances or hyporeflexia may be present in 25% of cases (02; 30; 34; 53).
Clinical variants. Patients with cholinergic dysautonomia have prominent parasympathetic impairment (abdominal pain, vomiting, obstipation, ileus, fixed heart rate, urinary retention, dilated unreactive pupils, loss of accommodation). Sympathetic dysfunction is restricted to postganglionic cholinergic sudomotor fibers. Orthostatic hypotension is not observed. The evolution of this disease is similar to acute pandysautonomia, although it affects a younger age group (reported age of onset is 6 to 24 years) and is associated with poor or incomplete recovery (01). A similar but more chronic and milder presentation is seen in Lambert Eaton myasthenic and Sjogren syndromes.
A restricted syndrome with isolated impairment of gastrointestinal motility in the form of acute or chronic intestinal pseudo-obstruction has been described; 5% to 10% of cases have positive intermediate titer of gAChR antibodies (27; 29; 53). The other term used is “autoimmune gastrointestinal dysmotility” (AGID), which is also a limited manifestation of autoimmune dysautonomia, either idiopathic or paraneoplastic, and which can present with an acute onset. Gastroparesis, colonic inertia, and intestinal pseudo-obstruction have been described. Antibodies sought in this condition include ANNA-1 (anti-Hu), gAChR, and peripherin (10).
Patients with acute autonomic and sensory neuropathy have otherwise typical acute pandysautonomia, associated with various degrees of somatic sensory neuropathy (28; 29). Central nervous system involvement may occur in this entity, and psychiatric symptoms, galactorrhea amenorrhea syndrome, and anorexia can be seen. It is likely, however, that this is a different disorder altogether from acute autonomic ganglionopathy. This concept may be supported by newer observations and the discovery of new antibodies (23; 38).
Acute sensory autonomic neuronopathy (ASANN). Acute loss of all sensory modalities and pain in a non-length dependent distribution, absent corneal reflexes, areflexia, and sensory ataxia may be observed in patients (62; 29; 18). Limb and facial automutilation can occur. There is failure of adrenergic sympathetic and cholinergic as well as parasympathetic functions. There is motor weakness on careful examination. There is Wallerian degeneration of both short and long ganglionic fibers. The former leads to abnormal posterior cord MRI lesions (“inverted V sign”).
Acute autonomic sensory and motor neuropathy (AASMN) has also been reported as a subtype of acute autonomic neuropathy, but this syndrome seems to be clinically indistinguishable from Guillain-Barre syndrome (GBS) with prominent dysautonomia. In this variant there is definite muscle weakness.
Seronegative autoimmune autonomic neuropathy was described as a clinical entity separate from autoimmune autonomic ganglionopathy, including prominent sensory symptoms, orthostatic hypotension, and gastrointestinal symptoms (16). Testing showed prominent sympathetic failure, and no premature pupillary redilation was seen (25). Three out of six patients responded to intravenous steroids and not to plasma exchange, intravenous immunoglobulins, or rituximab.
Peripherin IgG-associated autonomic and somatic neuropathy and endocrinopathy affecting thyroid, pancreas, or ovaries has also been described (04). Fifty-four percent of the seropositive patients had dysautonomia with a predominance of gastrointestinal dysmotility, and 30% had neuropathic symptoms.
A syndrome of idiopathic postural orthostatic tachycardia associated with symptoms of light-headedness, postprandial bloating, abnormal sweating, and gastrointestinal motility may be a more restricted form of an autonomic neuropathy and may mimic acute pandysautonomia (42).
The disease is self-limiting but quite disabling, and partial or complete recovery occurs slowly over several months to years (64; 30; 47). Patients positive for gAChR antibody have more gastrointestinal dysmotility, sicca symptoms, and impaired pupillary function compared to seronegative autoimmune autonomic ganglionopathy patients (41). One third of patients make a good functional recovery, another third has a partial recovery with substantial deficits, and the remainder does not improve (47; 08).
The level of gAChR antibody may predict severity of illness and approach to therapy. Serum antibody level has been evaluated in the context of the severity of autonomic testing abnormalities as measured by CASS (composite autonomic scoring scale) (05). Antibody levels equal to or larger than 0.40 nmol/L predict severe autonomic dysfunction on autonomic testing (CASS> 7), with a sensitivity of 56% and specificity of 92%. Antibody titer equal to or higher than 0.20 nmol/L predicts moderate autonomic dysfunction on autonomic testing (CASS> 4), particularly if 25% anhidrosis on thermoregulatory sweat test (TST) is present. Antibody titer less than 0.20 nmol/L was not predictive of presence or absence of autonomic testing abnormalities and can be present in 2% to 4% of healthy controls (53). A level greater than 0.40 nmol/L predicts orthostatic hypotension, with 91% specificity but low sensitivity (38%).
Residual deficits may be mild in the form of sweating and pupillary abnormalities or more significant, eg, orthostatic hypotension, impotence, postprandial diarrhea, micturition disturbances, and paroxysmal coughing (30). Occasionally, cognitive impairment becomes apparent on resolution of the acute phase and is correlated with postural hypotension as well as an elevated gAChR antibody level (11).
For patients with acute sensory autonomic neuronopathy there is no appreciable improvement over time, which follows a rapid initial deterioration of both sensory and autonomic functions (18).
The patients are at risk for sustaining injuries from falls and developing urinary tract infection or aspiration pneumonia. Hydronephrosis may develop secondary to atonic bladder (64). Malnutrition and weight loss may result from anorexia, dysphagia, and diarrhea. Theoretically these patients may be prone to develop cardiac arrhythmias or asystole, and one instance of sudden cardiac arrest has been reported (45).
A 58-year-old woman had an acute onset of a diarrhea that resolved over 3 days. Two weeks later she started having abdominal pain, could not pass gas, and stopped having bowel movements. She was admitted to the hospital for further workup and treatment. Uncontrolled constant nausea, early satiety, and vomiting occurred, leading to inability to eat. She also developed presbyopia, dry eyes and mouth, and orthostatic hypotension with a few syncopal spells. While admitted, she developed urinary retention and mild tingling in her feet and hands.
Her vital signs were supine blood pressure 100/60 and pulse 92; blood pressure 60/40 and pulse 96 standing after 2 minutes; axillary temperature 37 degrees Celsius; respiratory rate 16; and weight 72 Kg.
Examination showed pale, dry skin with lack of moisture, resting tachycardia with normal heart sounds, and abdominal distension with diffuse tenderness and absent bowel sounds. An indwelling urinary catheter was in place. Neurologic examination showed intact mental status, fixed dilated pupils, dry eyes and mouth, but otherwise intact cranial nerves. Motor examination was normal, reflexes were preserved, and there was only mild distal pin loss in the hands and feet. Coordination was normal and gait was impaired by profound postural hypotension.
Autonomic testing showed abnormally low quantitative sweat responses at all sites, thermoregulatory sweat testing showed near complete anhidrosis, and she had reduced heart rate variability to deep breathing. Valsalva maneuver showed reduced baroreflex mediated heart rate response and abnormal beat to beat blood pressure responses with a prominent drop in blood pressure in early phase 2, absent late phase 2 and 4. Head up tilt table testing showed an immediate drop in blood pressure lacking compensatory tachycardia and leading to a syncopal event. Electromyography was normal.
Ganglionic acetylcholine receptor antibody titer was elevated at 2.40 nmol/L. PET scan failed to reveal a primary malignancy.
In addition to supportive treatment including psychological support midodrine, fludrocortisone, bethanechol, parenteral nutrition, and bladder catheterization, the patient was treated with a course of plasmapheresis 3 times per week for 2 weeks followed by weekly treatments for 3 weeks. This was associated with gradual improvement in symptoms paralleling lower gAChR antibody titer in the serum to 0.6 nmol/L. There was, however, residual constipation, urinary frequency, and orthostatic hypotension requiring a stable dose of midodrine one year later.
• Ganglionic acetylcholine receptor antibodies are responsible for the pandysautonomia in at least 50% of the patients.
The etiology of acute pandysautonomia is unknown. It is an acquired disorder with no known familial or genetic influences. Occurrence after a specific viral illness such as herpes simplex, Epstein Barr, cytomegalovirus, rubella, and with interferon alpha-2b therapy has been reported (03; 22). An association of acute pandysautonomia with other immunologic disorders and malignant neoplasms has been observed (54; 56). Several characteristics of the disease are consistent with an immune-mediated process. These include (a) preceding illness, subacute progression, and recovery; (b) elevated CSF protein levels; and (c) the presence of lymphocytic infiltrates in the autonomic and sensory ganglia. Advances have provided evidence for an autoimmune pathogenesis of acute pandysautonomia. Fifty percent of cases are positive for gAChR antibodies. Ganglionic acetylcholine receptor antibodies cause autonomic failure in both active and passive transfer animal models (57; 55; 27; 53). Antibody mediated internalization and depletion of cell surface AChR leads to reduced acetylcholine quantal size and, thus, loss of ganglionic transmission (59; 60). Importantly for treatment, the serum antibody level is significant as reduction past a certain point is needed for ganglionic transmission recovery. Based on current understanding of clinical and pathologic features, acute pandysautonomia (autoimmune autonomic neuropathy/ganglionopathy) may be primary or occur in the setting of malignancy or connective tissue disease. Seronegative cases may present in a similar fashion but may not respond to same treatment modalities (21; 26).
The incidence of acute autonomic ganglionopathy is unknown. There are no large prospective studies of this condition. From small series, the mean age of patients with autoimmune autonomic ganglionopathy is 61 years, with a slight female preponderance (27). The disorder has been diagnosed in children, pregnant women, and in the elderly.
The cholinergic form of this syndrome seems to have a pediatric predilection.
There are currently no preventative measures that can be employed.
Acute pandysautonomia needs to be distinguished from other disorders with predominant autonomic involvement. Given visceral involvement, usually medical and surgical organ-based diagnoses are usually ruled out first. Thereafter careful examination should help define the phenotype better and aid in further decision-making regarding testing and treatment.
Drug-induced (vincristine, cisplatin, taxol, doxorubicin, ARA-C, amiodarone), metabolic, and toxic (organic solvents, marine toxins) autonomic dysfunction syndromes are typically easy to differentiate given the temporal association. A more difficult to diagnose and relatively new entity is the treatment-induced acute autonomic neuropathy of diabetes (13; 32). This may occur in up to 10% of diabetic patients treated for uncontrolled hyperglycemia and subsequent substantial drop in glycosylated hemoglobin levels. Symptoms include neuropathic pain along with parasympathetic and sympathetic dysfunction.
Paraneoplastic dysautonomia closely resembles idiopathic pure dysautonomia and is difficult to distinguish, especially in the absence of overt malignancy. The disorder is, however, relentlessly progressive but may stabilize with specific treatment of the underlying malignancy. Most common malignancy is small cell lung cancer, but thymoma, breast cancer, and lymphoma should also be considered (56). Paraneoplastic antibodies (anti-HU or ANNA-1, amphiphysin, and anti-CRMP-5 or anti-CV2) in serum or spinal fluid and imaging for a tumor including PET scan should be considered (07; 06). Lambert-Eaton myasthenic syndrome is another example of an autoimmune autonomic disorder. It can be either paraneoplastic or primary autoimmune in nature. The disorder combines fatigable proximal muscle weakness with typically mild cholinergic dysfunction in two thirds of patients: dry mouth, constipation, impotence, tonic pupils, impaired sweating, and positive antibodies for P/Q voltage gated calcium channel antibodies. Autonomic symptoms may precede the onset of weakness. Syndromes of muscle fiber hyperexcitability (Isaac or Morvan syndrome, stiff person syndrome) are typically associated with autonomic hyperactivity: hyperhidrosis, tachycardia, and hypertension.
Acute pandysautonomia is clearly distinct from autonomic failure seen in alpha synucleinopathies. The latter are chronic and progressive, with later age of onset and predominant sympathetic and parasympathetic dysfunction, but typically usually with less prominent enteric system involvement (39).
Patients with sensory autonomic ganglionopathy (ASANN) and GBS variants with autonomic symptoms and signs (AASMN) require careful clinical examinations for a correct diagnosis.
Various initial symptoms of acute pandysautonomia, such as dryness of the mouth, visual difficulties, fainting spells, impotence, and insomnia may be erroneously diagnosed as a psychiatric disorder. Syncopal episodes may be attributed to cardiac causes unless other autonomic abnormalities are appreciated. Prominent cholinergic dysfunction early in the disease presenting as "acute abdomen" has led to a laparotomy because of a presumed diagnosis of ileus or intestinal obstruction.
Autoimmune connective tissue disorders have also been associated with pure autonomic neuropathy (20). Systemic lupus erythematosus, mixed connective tissue disorder, scleroderma, rheumatoid arthritis, and Sjögren syndrome are the more common ones (08). The latter should be ruled out in all cases of an acute or subacute autonomic and sensory neuropathy.
Acute pandysautonomia may be accompanied by mild sensory or motor disturbances, and appropriate electrophysiological and biochemical investigations may be required to distinguish it from other autonomic-sensory polyneuropathies such as diabetes mellitus, porphyria, and amyloidosis. Hepatic porphyrias can present with acute abdominal pain and ileus, nonascending asymmetric motor neuropathy, and early parasympathetic followed by sympathetic dysfunction. The autonomic symptoms seen in Guillain Barre syndrome may take form of autonomic hyperactivity due to more prominent afferent lesions: resting tachycardia, arrhythmias, excessive peripheral vasoconstriction, and hypertension. Urinary retention and gastrointestinal dysmotility have also been described. If no etiology is apparent, a search for an occult cancer is always warranted.
The diagnosis is primarily based on recognizing the acute or subacute development of widespread autonomic dysfunction with attention to central nervous system or peripheral somatic nerve involvement. Testing aimed at primary specific organ pathology is completed first and includes blood work and gastrointestinal endoscopy and imaging and motility studies.
Autonomic function can be quantitated by using a composite autonomic scoring scale, which may also be useful in monitoring the progress of the disease (47). This includes autonomic reflex screen testing: thermoregulatory sweat testing, quantitative sudomotor axon reflex testing (QSART), beat to beat blood pressure measurements and hear rate measurements during Valsalva maneuver, and head up tilt table testing. EMG and nerve conduction studies are usually normal in AAG but should be performed if there are somatic sensory or motor manifestations. In ASANN sensory nerve conduction studies show either absent or low amplitude normal velocity responses (18). CSF protein is elevated in most patients, but intrathecal IgG synthesis has not been observed. Relevant biochemical and imaging studies may be needed to rule out disorders such as diabetes mellitus, porphyria, systemic lupus erythematosus, and a malignant tumor that may be associated with the autonomic disturbances.
Basal plasma level of norepinephrine is low and does rise on standing, but the response may be blunted. Denervation supersensitivity can be tested by low-dose intravenous infusion of norepinephrine. 6 fluoro-dopamine positron emission tomographic or meta-iodobenzylguanidine cardiac imaging can be used to identify cardiac sympathetic denervation.
Microneurography, skin biopsies for intraepidermal and sudomotor nerve fiber densities, nerve biopsy, lip biopsy, and immunohistochemical studies are employed to understand the pathophysiology and may be useful for providing a more definitive diagnosis but also rule out other conditions. If clinically indicated, a rectal biopsy or sural nerve biopsy may be performed to rule out amyloidosis.
Our current radioimmunoprecipitation assay has two problems: low sensitivity and low specificity. The prevalence of gACHR antibodies in AAG is not known. Serum gAChR antibodies have been reported in about 50% of patients with acute or subacute pandysautonomia. Conversely low titer gACHR antibodies are found in other conditions where they are not clearly pathogenic. The antibody is pathogenic through receptor immunomodulation. Association between a positive antibody status and HLA-DRB1*0403 allele has been reported (31). Higher autoantibody levels correlate with severity of symptoms and with predominant cholinergic dysautonomia. It is important to mention here that the gAChR exist in the hypothalamus and have other functions to include modulation of dopamine function as well as hypothalamic pituitary axis activity (37). Current methodology employs radioimmunoprecipitation (RIP) using labeled epibatidine, which binds only to the pentamer unit of the gAChR (36), thus, identifying only the alpha 3 subunit of the receptor. Another technique of luciferase immunoprecipitation (LIP) has similar sensitivity and can also detect antibodies to the beta 4 subunit, which are less common than alpha 3 subunit (38). The beta 4 subunit is also essential for autonomic ganglionic transmission, and antibodies to this subunit may be responsible for the presence of additional symptoms (37). Both techniques, radioimmunoassay and luciferase immunoprecipitation, rely on immunoprecipitation of the neuronal gAChR antibody and do not provide a functional readout of the antibody pathogenicity. Both assays may detect intracellular portions of the receptor and, thus, generate false-positive results. The luciferase immunoprecipitation assay has major limitations due generalizability and limited specificity (50). Two other methods designed to increase specificity have been developed but are not commercially available. A flow cytometric-based assay, which determines antibody immunomodulation, has perfect concordance with the radioimmunoassay-based method and seems to eliminate false-positive results (51; 50). A more specific live cell-based assay has also been developed (24).
The syndrome of paraneoplastic dysautonomia is clinically indistinguishable from idiopathic acute or subacute pandysautonomia; however, it is often associated with ANNA-1 (anti-Hu) and CRMP-5 antibodies (27; 56; 41; 52). Seropositivity for these specific autoantibodies in patients with insidious onset of pandysautonomia may also help distinguish from degenerative causes of autonomic failure (09). In cases of autoimmune gastrointestinal dysmotility, a complete serum paraneoplastic panel is recommended.
Like any other autoimmune marker, ganglionic nicotinic receptor antibodies may also be seen as a nonspecific marker of autoimmunity and can be positive in cancer and hypergammaglobulinemia. In a large series these antibodies were seen in myasthenia gravis, celiac disease, and other autoimmune neurologic syndromes (05; 53).
Various testing modalities have aided understanding of the mechanisms of pandysautonomia. Midposition, unreactive pupils are due to a loss of both sympathetic and parasympathetic innervation. Pharmacologic autonomic testing in pandysautonomia is consistent with denervation supersensitivity due to postganglionic involvement. Pupillary reactions show prompt constriction to instillation of 2.5% methacholine or 0.1% pilocarpine, dilatation with 0.1% epinephrine, and no response to 4% cocaine. Low doses of norepinephrine or epinephrine produce exaggerated hypertensive response, and subcutaneous carbachol causes a marked increase in intravesical pressure, profuse salivation, sweating, and abdominal colic (64; 30).
Other parasympathetic tests show paralysis of accommodation, reduced salivation, lacrimation (Schirmer less than 15 mm), abnormalities on cystometrogram, and gastrointestinal motility studies (30). Electromyography, nerve conduction, and H-reflex studies are usually normal; however, sympathetic skin responses may be absent (45). One study evaluated sudomotor dysfunction in patients with autoimmune autonomic neuropathy, using the thermoregulatory sweat test (TST) and quantitative sudomotor axon reflex test (QSART) (26). A postganglionic lesion (abnormal TST, abnormal QSART) was noted in the majority of patients and a preganglionic pattern (abnormal TST, normal QSART) in only 4 out of 21 patients. The distribution of anhidrosis was noted to be segmental, regional, global, or predominantly distal, consistent with a combined pattern of ganglionopathy and distal axonopathy.
Sural nerve biopsies have demonstrated a reduction of small myelinated and unmyelinated fibers, axonal sprouting, and the presence of epineurial mononuclear cell infiltrates (02; 64; 30; 45; 47). Examination of biopsied specimens from a child with acute pandysautonomia who underwent laparotomy for intestinal pseudo-obstruction showed an absence of ganglion cells in the appendix, hypoganglionosis in the rectal wall, and mononuclear inflammatory infiltrate in the region of the myenteric plexus (03). An autopsy in a patient with acute pandysautonomia who died following a sudden cardiac arrest revealed numerous lymphocytic infiltrates with a mixed population of T cells and B cells in the autonomic and sensory ganglia and, to a lesser extent, in the nerve roots, spinal cord, and parahippocampal region (45). Autopsy cases also revealed loss of cell bodies in thoracic sympathetic, Auerbach plexus, and dorsal root ganglia extending to the dorsal columns in more severe cases (29).
The treatment is mainly symptomatic and supportive at first. A high degree of suspicion for an autoimmune etiology is required in order to start early immunomodulatory therapies, particularly in seropositive cases, with the hope of limiting disability and improving outcome. There are, however, currently no prospective randomized trials of immunomodulating therapies for this condition.
In seropositive AAG cases, acute intravenous immunoglobulins and plasmapheresis and more chronic oral immunosuppressive medications have shown benefit in small series. Rituximab has also shown promise in a handful of cases (53).
Midodrine hydrochloride, an alpha-adrenergic agonist is useful in the treatment of neurogenic orthostatic hypotension. An effective dose is 10 mg two to three times daily (61). Fludrocortisone also can provide moderate relief of orthostatic hypotension. The major drawback of treatment with midodrine hydrochloride or fludrocortisone is the resultant supine hypertension. Another approach to treatment of orthostatic hypotension is pyridostigmine bromide, an acetylcholine esterase inhibitor, which enhances sympathetic ganglionic transmission. Open-label and randomized controlled trials of pyridostigmine for treatment of neurogenic orthostatic hypotension showed improvement in orthostatic symptoms and blood pressure without significant supine hypertension. These studies included patients with a variety of causes for neurogenic orthostatic hypotension, including patients with autoimmune autonomic neuropathy as well (44; 43).
Head elevation at night past 30 degrees; elastic stockings and other support garments for the lower half of body, including the abdomen; and improving the red cell mass by giving erythropoietin may be helpful. L-DOPS (droxidopa) has been used as long-term therapy in acute pandysautonomia and was reported to be effective in a patient with severe, refractory orthostatic intolerance (15) but is not FDA-approved for this indication.
Parasympathomimetic drugs like carbachol and bethanechol relieve bowel, bladder, and pupillary symptoms. Treatment should be begun with low doses to avoid side effects. During the acute phase of the illness, patients may require nasogastric suctioning, intravenous fluids, and parenteral nutrition. Artificial tears, saliva, bifocal corrective lenses, bladder catheterization, and enemas may alleviate discomfort. Enteral feeding tubes and parenteral nutrition may be employed in order to avoid protein calorie malnutrition.
Acute sensory autonomic neuronopathy has limited if any response to immune modulating agents and alpha blockers (midodrine) but may have a surprisingly good response to low doses of droxidopa due to denervation supersensitivity (18).
• Most acute pandysautonomia disorders have profound functional loss, prolonged hospitalizations, and poor functional outcome.
No definitive long-term treatment is available due to lack of randomized controlled studies. Most immunomodulatory treatments have been employed in antibody positive autoimmune autonomic ganglionopathy cases, although few antibody-negative cases have been treated with improving function (21). Oral glucocorticoid therapy led to dramatic relief in one patient (64), and a partial response to intravenous methylprednisolone pulse treatment has been reported (45). Several reports have documented significant and prompt response to intravenous immunoglobulin (IVIG) therapy, although in the 3 patients reported by Gibbons and colleagues, short-term treatment with intravenous immunoglobulin or plasmapheresis did not produce any benefit (14). A similar beneficial response to IVIG was also noted in a patient with variant syndrome of acute autonomic sensory and motor neuropathy and was accompanied by increased plasma renin and norepinephrine levels (49). In a series of six patients with subacute or chronic pandysautonomia (including two patients seronegative for ganglionic AChR antibody), treatment with IVIG or plasmapheresis alone resulted only in partial or transient benefit. However, addition of an immunosuppressive agent such as prednisone, azathioprine, and particularly mycophenolate mofetil led to significant long-term improvement (21). Six months of treatment with oral mycophenolate mofetil, high dose oral prednisone, and five plasma exchanges produced significant improvement in function despite the patients being symptomatic for up to 2 years (14). Two pediatric patients treated with rituximab showed positive responses (48). A retrospective study from Japan suggested that combination therapy with intravenous methylprednisolone, intravenous immunoglobulins, and followed by oral prednisolone was superior to monotherapy as the rate of improvement in the total number of symptoms was higher in patients with combined therapy than in patients with non-combined therapy (70.7% vs. 28.6%) (19). Bladder dysfunction, as also reported by others, tended to respond less compared to other autonomic symptoms.
Conclusions drawn are limited by retrospective evaluation of small sample sizes, but in considering immunomodulatory therapy for autoimmune autonomic ganglionopathy, one should start treatment despite long-term duration of symptoms and continue treatment for at least 6 months with a combination of agents aimed at lowering gAChR antibody titers below 1.00 nmol/L. A combination of steroids and intravenous immunoglobulins may be more effective than treatment with a single drug.
Normal pregnancy and delivery occurred in a patient with cholinergic dysautonomia, although she had a precipitated labor (01). One patient in the series by Koike and colleagues developed symptoms while pregnant and a Caesarean section was performed (28).
Perioperative interventions have to take into account severity of autonomic failure and type of scheduled procedure. Decision for regional versus general anesthesia is an early one. Preoperative intravascular volume restoration and use of induction agents that produce minimal cardiovascular changes are useful. Close blood pressure and heart rate monitoring, treatment of blood pressure swings and arrhythmias, consideration towards holding blood pressure supportive medications preoperatively, mucosal protection given dryness, and treatment of hypothermia will be needed. Knowledge of the possibility of denervation hypersensitivity should drive the choice for short-acting, low-dose vasoactive agents to support blood pressure and heart rate. Opposite, autonomic denervation may cause relative unresponsiveness to low dose vasoactive agents. Avoidance of anticholinergic agents should be considered. Postoperatively, treatment of prolonged ileus and urinary retention as well as hypotension and hypothermia are needed (35).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Alexandru C Barboi MD FACP
Dr. Barboi of NorthShore Medical Group has no relevant financial relationships to disclose.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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