Autonomic Dysfunction in Iraqi Patients with Chronic Inflammatory Demyelinating Polyneuropathy

Objective:The purpose of this study is to evaluate the autonomic disturbance in patients with chronic inflammatory demyelinating polyneuropathy.Methods:Thirty-eight patients who fit into the AAN criteria of diagnosis of CIDP were studied. Five standard cardiovascular autonomic Ewing tests were performed for every patient in addition to the assessment of autonomic symptoms.Results: The study includes 32 males and 6 females their age ranged from 10 to 69 years. In this study we have seen one child with CIDP whose age was ten years and he had PST impairment. Sexual disturbance was the majorautonomic symptom seen in the males [40.6%], while urinary disturbance 2was the major autonomic disturbance encountered in females [66.6%]. Autonomic function tests [AFT] showed that one quarter of males and half of the females had abnormal AFT. In patients aged between 50-59 years, [40%] having normal autonomic function test, [40%] had PST impairment, while the others have mixed impairment [20%]. None of the patients had pure sympathetic impairment. Regarding the types of CIDP the largest percent [84.2%] of patients have classic type of CIDP while 7.8%, 5.2% and 2.6% had DADS, MADSAM and MMN respectively.Conclusions: Autonomic dysfunction was common in Iraqi CIDP patients. PST impairment is a major pattern of dysautonomia in CIDP. Sexual disturbance in males while urinary disturbance in females were the most common autonomic symptoms encountered. VM, HR response to standing allow an early detection of autonomic dysfunction even in asymptomatic individuals.


Definition
The term chronic inflammatory demyelinating polyradiculoneuropathy [CIDP] has been used to identify patients with a chronically progressive or relapsing symmetric sensorimotor disorder with cytoalbuminologic dissociation and interstitial and perivascular endoneurial infiltration by lymphocytes and macrophages. In many ways, CIDP can be considered the chronic equivalent of acute inflammatory demyelinating polyradiculoneuropathy [AIDP], the most common form of Guillain-Barré syndrome [GBS]. [1]

1-Classic CIDP:
Classic chronic inflammatory demyelinating polyradiculoneuropathy [CIDP] is characterized by the occurrence of symmetrical weakness in both proximal and distal muscles that progressively increases for more than two months. The condition is associated with impaired sensation, absent or diminished tendon reflexes, an elevated cerebrospinal fluid protein level, demyelinating nerveconduction studies, and signs of demyelination in nerve-biopsy specimens. The course can be relapsing or chronic and progressive, the former being much more common in young adults. [2][3][4] 2

-Distal Acquired Demyelinating Symmetric Neuropathy [DADS]: Autonomic Dysfunction in Patients with CIDP Introduction
It has been suggested that distal acquired demyelinating symmetric neuropathy is a distinct acquired demyelinating polyneuropathy. [5] Features of the disorder include an increased prevalence in men and in persons over the age of 50 years, a predominantly distal sensory loss, a mild distal weakness (as opposed to the more generalized motor deficits in classic chronic inflammatory demyelinating polyneuropathy), and an unsteady gait. IgMparaproteinemia is present in nearly two thirds of patients with this condition. [6] IgM-associated distal demyelinating symmetric neuropathy seems to respond poorly to immunosuppressive therapy. [6] 3

-Multifocal Motor Neuropathy [MMN]:
Multifocal motor neuropathy is characterized by asymmetric weakness without sensory loss, often starting in distal arm muscles. A partial motor-conduction block at multiple sites is a characteristic electrophysiologicfeature, although not all patients have this finding. Cerebrospinalfluid protein levels and cell counts are usually normal. Although corticosteroids and plasmapheresis are ineffective treatments, multifocal motor neuropathy improves with immune globulin [7] or cyclophosphamide [8] therapy.

4-Multifocal Acquired Demyelinating Sensory and Motor Neuropathy the [Lewis-Sumner Syndrome]:
Multifocal acquired demyelinating sensory and motor neuropathy [the Lewis-Sumner syndrome]has similarities to both chronic inflammatory demyelinating polyneuropathy [i.e., motor and sensory deficits, an elevated protein content, and abnormal results on motor-nerve and sensorynerveconduction studies] and multifocal motor neuropathy [i.e., asymmetrical presentation of symptoms, often starting from the arms and hands, and conduction block]. [9][10][11]. Some patients with the condition have antibodies to gangliosides, [12] and these patients have a reasonably good response to treatment with intravenous immune globulin or cyclophosphamide.

Historical Background
Eichhorst [13] first described recurrent polyneuritis in 1890. Sporadic case reports followed, including a case series by Hoestermann in 1914 that described a 50-year-old man who experienced 6 bouts of polyneuropathy between 1870 and 1900. A report from 1929 that describeda case of recurrent polyneuropathy in a 45-year-old man further demonstrates the cardinal clinical features of relatively symmetric proximal and distal weakness, hyporeflexia or areflexia, and to a lesser degree, sensory disturbances. [4] Elevation of cerebrospinal fluid protein without pleocytosis[albuminocytologic dissociation] was reported in a case of relapsingpolyneuritis in 1931. Fifteen years earlier, Guillain, Barre´, and Strohlhad reported this laboratory finding in 2 French soldiers with acute polyneuritis. [15] The concept of segmental demyelination causing conduction block was not new, having been reported by Denny-Brown and Brenner [15] following experiments with tourniquet paralysis of the cat sciatic nerve. Segmental demyelination was later found to be the predominant histopathologic feature of the human sural nerve in cases of CIDP. [16] In 1975, Dyck and colleagues proposed diagnostic criteria in a landmark publication that described 53 patients with "chronic inflammatory polyradiculoneuropathy." [17] In 1958, Austin was separated CIDP from acute inflammatory polyradiculoneuropathy, or GBS, on the basis of a prolonged and relapsing course and responsiveness to corticosteroids. [17,18]

Epidemiology
Chronic inflammatory demyelinating polyneuropathy is a common, albeit under diagnosed and potentially treatable disease with an estimatedprevalence of about 0.5 per 100,000 children [19] and 1 to 2 per 100,000 adults. [20,21].
Other studies report a prevalence of 2-7.7/100,000. [20,22]This would correspond to approximately 5,000 to 22,000 cases in the United States.
This degree of variance underscores the difficulties associated with the diagnosis of CIDP.
Both sexes are affected equally. MMN has male-female predominance of at least 2:1 based on a survey of the largest case series. [23] CIDP may occur at any age, but it is more common in the fifth and sixth decades. Relapsing course is associated with younger age of patients [third and fourth decades]. CIDP has been described in childhood. [24]

Pathophysiology
CIDP is presumed to occur because of immunologic antibody-mediated reaction along with interstitial and perivascular infiltration of theendoneurium with inflammatory T cells and macrophages. The consequence is a segmental demyelination of peripheral nerves. [25] Human leukocyte antigens Dw3, DRw3, A1, and B8 occur more frequently in patients with CIDP than in the healthy population. [25]

Etiology
CIDP is most frequently an idiopathic illness, but it has been known to occur with several conditions. In those cases, the associated condition is included in the main diagnosis [for example, CIDP with paraproteinemia, CIDP with HIV infection] to separate those cases from the idiopathic variety Most reported conditions associated with CIDP are listed below: [26] -HIV infection: In these patients, mild lymphocytic pleocytosis and increased gamma globulin level in the CSF are seen frequently.
-Hodgkin lymphoma. Neuropathy associated with Inflammatory Demyelinating Polyneuropathy Hodgkin lymphoma is not caused by direct infiltration of the peripheral nerves but is a consequence of the autoimmune cascade that occurs with this disease; the mechanism is not completely clear.
-Paraproteinemias and/or plasma cell dyscrasias a-CIDP is seen with monoclonal gammopathies [eg, monoclonal gammopathy of unknown significance [MGUS]), most frequently gammopathy of immunoglobulin M [IgM]. Evidence exists to suggest that CIDP with IgM MGUS has specific clinical and electrophysiologic characteristics. Patients usually have predominance of distal weakness, for example, and sensory symptoms are greater than motor. [27] b-Some paraproteinemias occur as isolated phenomena and some are by-products of malignant cells, as in the cases of Waldenströmmacroglobulinemia and myeloma. In myeloma-associated neuropathy, theabnormal paraprotein usually consists mostly of lambda light chain component. Combination of osteosclerotic myeloma, organomegaly, endocrinopathy, M protein, sensorimotor neuropathy, and pigmentary skin changes is referred to as POEMS syndrome. In POEMS syndrome, the M protein is typically immunoglobulin G [IgG].
-Inflammatory bowel disease: CIDP has been described in association with Crohn disease and other inflammatory bowel conditions, although no direct correlation between the 2 afflictions is known.
-Diabetes mellitus: Increasing evidence supports the suggestion that some patients with diabetes who have severe neuropathy or unusually progressive neuropathy may have CIDP superimposed on their diabetic disorder. [28,29] -Occasionally, chronic inflammatory demyelinating polyneuropathy may develop in a setting of another polyneuropathy, even one with ahereditary basis, such as Charcot-Marie-Tooth disease. [30]

History
CIDP most frequently starts insidiously and evolves slowly, either in a slowly progressive [more than 60% of patients] or relapsing manner [approximately one third of patients], with partial or complete recovery between recurrences. Periods of worsening and improvement usually last weeks or months. Initial symptoms include weakness of the limbs, both proximal and distal, with proximal muscles affected at least as severely as distal. Sensory symptoms are common.
Only a small proportion of patients approximately 16% have a relatively acute or subacute onset of symptoms, with subsequent steadily progressive or fluctuating course.
Most experts consider the necessary duration of symptoms to be 8-12 weeks for the diagnosis of CIDP to be made.

Physical examination
Depending on the associated systemic disorder, abnormalities on physical examination may be found in multiple organ systems. Patients should be examined in detail for signs of autoimmune, inflammatory, and neoplastic conditions.
Cranial nerves: Cranial nerves may be involved, particularly CN VII, with paralysis of both upper and lower facial muscles. Diplopia can occur with the involvement of CN III, IV, or VI. Rarely, bulbar muscles [e.g., palate, tongue] can be affected.
Papilledema with pseudotumorcerebri syndrome are observed rarely in patients with CIDP and are due to a very high CSF protein level Gait: Gait frequently is abnormal.
Motor system: Usually relatively symmetric weakness of both proximal and distal muscles is present in upper and lower extremities. Muscle tone can be normal or decreased. Hypotonia, atrophy, and fasciculations may be present. Deep tendon reflexes characteristically are diminished or absent even in regions with only mild weakness.
Sensory system: Large-diameter, heavily myelinated fibers are affected most severely, leading to proprioceptive and vibratory deficits. Loss or decrease of pain [i.e., pinprick] and temperature sensations is less common. Stocking-glove distribution of sensory deficits is typical. Neuropathic pain in affected extremities may occur. [3,17]

Neurotransmitters
Acetylcholine [Ach] is the preganglionic neurotransmitter for both divisions of the ANS as well as the postganglionic neurotransmitter of PST neurons. Nerves that release Ach are said to be cholinergic.
Norepinephrine [NE] is a neurotransmitter of postganglionic ST neurons; these nerves are said to be adrenergic. Within the ST outflow, postganglionic neurons innervating the eccrine sweat glands [and perhaps some blood vessels supplying skeletal muscles] are of cholinergic type [38].

The Functions of ANS
The ANS innervates vascular and visceral smooth muscles, exocrine and endocrine glands and parenchymal cells throughout the various organ systems. Functioning below the conscious level, the ANS respond rapidly and continually to perturbations that threaten the constancy of the internal environment.
The many functions governed by this system include the distribution of blood flow and the maintenance of tissue perfusion, the regulation of blood pressure, the regulation of volume and composition of extracellular fluid, the expenditure of metabolic energy and supplying substrate, and control of visceral smooth muscles and glands [38,39].

Autonomic Testing
The functional characteristics of ANS can be assessed by physiologic and pharmacological tests. When autonomic neuropathy is suspected, non-invasive tests can be used initially to confirm the diagnosis, and to determine whether ST or PST pathways, or both are involved.
In some cases further studies requiring intra-arterial catheterization may be needed to localize the site of the lesion in ANS more precisely [35,40], commonly used physiologic tests primarily assess the autonomic aspects of cardiovascular functioning. These tests are non-invasive, easy to use and provide quantitative or regional information about autonomic functioning.
Interpretation of results requires collection of data under controlled circumstances. In addition to five tests described by Ewing & Clarke [41], other tests are available, like cold pressure test, in which subjects immerse his hand in ice water and after one minute systolic and diastolic blood pressure normally rise by 10-20 mmHg.
Sudomotor functioning tests are used to assess the STpostganglionic fibers either as quantitative test [quantitative sudomotor axon reflex test] or as qualitative measure [thermo regulating sweat test] [42,43].
The pharmacological tests elucidate pathophysiological abnormalities, help to localize an autonomic defect to the central or peripheral NS and guide the development of rational therapy, for example, measuring of nor epinephrine levels in response to standing or by using drugs with presser activity e.g. Tyramine [35,40,42].

Aims of the Study
The aim of the study was to investigate: 1-The frequency of autonomic dysfunction in Iraqi CIDP patients.
2-The distribution of autonomic dysfunction in relation to age, sex and the types of CIDP

Subjects and Methods
Thirty-eight patients who fit into the AAN criteria of diagnosis of CIDP [4] were studied during the period between June 20015 and April 20016 in the Department of Neurology at, neurosciences hospital,baquba teaching hospital and neurosurgery hospital Baghdad Iraq.
The patients were diagnosed as clinically definite CIDP. Each patient was interviewed and assessed according to a protocol paper [appendix 1].
Every patient was fully examined neurologically, medically and electro physiologically. Cerebrospinal fluid was aspirated for every patient.
The patients were on no medications known to affect the autonomic functions. They are divided into six groups according to age, into two groups according to gender and into four groups according to the types of CIDP.
Five standard cardiovascular Ewing tests [41], were performed for every patient as shown in appendix 2, and these include:

Results
The study was performed on thirty eight clinically definite CIDP patients. In patient groups there were males and females.         Fifty percent of patients with classic type of CIDP presented with normal AFT but without symptoms, while 25% of them presented with normal AFT but with presence of symptoms, the rest are presented with abnormal AFT and complained of symptoms. 66.6% of DADS type patients presented with normal AFT and with presence of symptoms, while the rest presented with abnormal AFT but without symptoms.

Discussion
This is the first study investigating in details the autonomic dysfunction in Iraqi CIDP patients.
This study showed that the battery of ANS tests could be used in assessment of ANS abnormalities in CIDP patients, the most precise detection of autonomic reflexes can be achieved by using of the whole battery of tests.
In this study the total no. of males was five times more than the total no. of females; these findings did not match with other studies that showed that equal sex distribution in CIDP patients. [23] The majority of male patients with CIDP were in the 3rd decade of their life while no reported cases have been seen in the 7th decade. In contrast, third of females with CIDP were in the 7th decade, while no reported cases have been seen in the 3rd decade.
CIDP has been described in childhood [24]; in this study we have seen one child with CIDP whose age was ten years.
This study showed that the symptoms related to autonomic disturbances in CIDP were present in the vast majority of patients, even at the onset of the disease and showed a difference in distribution between males and females. Sexual disturbance was the main autonomic symptom in male patients with CIDP [40.6%], and approximately half of those patients had loss of early morning erection, while urinary disturbance was the major autonomic symptom in female patients [66.6%] followed by cardiovascular autonomic symptoms (half of the females).
In general, it's appeared that autonomic symptoms were more frequent in females than males apart from sexual disturbance.
The high frequency of autonomic symptoms found in this study should encourage the practicing clinician to look carefully for these abnormalities in the evaluation of the patients and not merely emphasize on the usual CIDP features, as these autonomic disturbances may be disabling and in most of the times, simple measures to overcome such disturbances may have great deal in helping the patients to improve their quality of life. [41] showed that one quarter of males and half of the females had abnormal AFT.

Autonomic function tests [AFT] done according to Ewing & Clarke
Pure PST impairment was seen in 21% of the study subjects and it was slightly higher in males than in females. Pure ST impairment was not seen in the study subjects. Mixed PST and ST impairment were seen in both males and females but it is much higher in females in comparison to males (33.3% in females and 3.1% in males).
Regarding the age of the patients; all patients aged between 10-19 years, 30-39 years and 60-69 years have PST impairment, normal AFT and mixed impairment respectively. At the age group between 20-29 years and 40-49 years; one quarter have PST impairment while the rest have normal AFT.
The heart rate response to VM and to immediate standing and blood pressure response to sustained handgrip had the disadvantage of being effort dependent, thus disabled patients may need help of others to overcome their disability. The cooperation of those disabled is essential to obtain satisfactory performance of the above tests. This fact should be consideredwhen CV reflexes are assessed. To overcome some of those disabilities, certain instruments have been developed to help in the assessment of the crippled patients.
A critical point in the assessment of autonomic functions was the age of the patients, as autonomic functions might be affected when the age advanced, this must be taken into consideration when the results are analyzed.
In this study, abnormal VM is the most common abnormality encountered followed by the heart rate variation on standing and then the heart rate variation on deep breathing. Also abnormal isometric test was more common than BP response to standing.
Regarding the types of CIDP, classic CIDP was a phenomenon being the most common type seen in this study (84.2%),while the other types are much less [15.8%]. Half of the patients with classic CIDP had normal AFT without autonomic symptoms; one quarter of them had also normal AFT but complained from symptoms such as loss of early morning erection. Towthird of patients with DADS had normal AFT and complained from autonomic symptoms while the rest onethird had abnormal AFT but they did not complained from autonomic symptoms. The patient with MMN had normal AFT but he complained from loss of early morning erection. All patients with MADSAM had abnormal AFT and complained from autonomic symptoms.
In this study, half of female patients had abnormal AFT and complained from autonomic symptoms, in contrast, approximately half of males patients had normal AFT with out complain of autonomic symptoms.

Conclusions
1-Autonomic dysfunction assessed by Ewing et. al. tests were common in Iraqi CIDP patients.
2-Dysregulation of PST cardiovascular control mechanism is a major pattern of dysautonomia in CIDP. Combined [ST and PST ] was less common in CIDP; were as pure ST affection was not seen in this illness.
3-Sexual disturbance in males while urinary disturbance in females were the most common autonomic symptoms encountered.
4-A simple test [VM, HR response to standing] that can be performed in outpatient setting allowing an early detection of autonomic dysfunction in those patients even in asymptomatic individuals

Recommendations
-Proper attention to the assessment and management of autonomic function in CIDP may help in improving the quality of life of those patients; as those disturbances are disabling and in most of the times, simple measures might be taken to overcome such impairment, thus the practicing clinician should be encouraged to look carefully for the autonomic symptoms when they assess their CIDP patients and not merely emphasize on usual CIDP features; because most of those symptoms were disabling and interfered with daily social life.
-Cardiovascular dysfunction may be considered a prognostic factor in the course of CIDP; a prospective study should be performed in order to determine its prognostic implication.
-The need for a special instrument designed to help the patient and the physician to overcome disabilities issues that are encountered in any chronic neurological disease like CIDP.

Appendix 2
The five standard cardiovascular Ewing tests used forassessment of cardiovascular autonomic neuropathy A-Tests to detect parasympathetic involvement: 1-Heart rate response to valsalva maneuver: the test is performedby asking the patient to blow into a mouth-piece connected to amodified sphygmo-manometer and holding it at a pressure of 40 mmHg for 15 seconds, while continues electrocardiogram isrecorded. The result are expressed as the valsalva ratio whichthe ratio of the longest R-R interval after the maneuver to theshortest R-R interval during the maneuver. The mean of the 3valsalva ratios is taken as the final value.
2-Heart rate (R-R interval) variation during deep breathing: thepatient sits quietly and breathes deeply and even at six breathsper minutes, with 5 seconds allocated for each inspiration andexpiration to optimize the sinus arrhythmia. Anelectrocardiogram is recorded throughout the period of deepbreathing, with a marker to indicate the onset of eachinspiration and expiration. The result is then expressed as themean difference between maximum and minimum heart rate forsix measured cycles in beats per minutes.
3-Immediate heart rate response to standing:the tests isperformed with the patient lying quietly on a couch while theheart rate is recorded continuously on an electrocardiogram.
The shotest R-R interval at or around the 15th beat and thelongest R-R interval at or around the 30th beat after starting tostand are measured. The characteristic heart rate response isexpressed by the 30:15 ratio (R-R interval of the 30th to the R-Rinterval of the 15th ).
B-Tests to detect sympathetic involvement: 1-Blood pressure response to standing: the test is performed bymeasuring the patient blood pressure with sphygmomanometerwhile he is lying down, and again when he stand up for threeminutes. The postural fall of blood pressure is taken as thedifference between systolic blood pressure lying and systolicblood pressure standing.
2-Blood pressure response to sustained handgrip: heresphygmomanometer cuff is used. Handgrip is then maintainedat the 30% of that maximum for as long as possible up to fiveminutes. blood pressure is measured three times before and atone-minute interval during handgrip. The result was expressedas the difference between the highest diastolic blood pressureduring handgrip exercise and the mean of the three diastolicblood pressure readings before handgrip begun.