Chronic inflammatory demyelinating polyneuropathy icd 9

Research Proposal: Nursing Interventions To Decrease Complications Of Diabetes

The dilemma of diabetes in chronic inflammatory demyelinating polyneuropathy

Vera Brila, Christopher M. Blanchetteb, Joshua M. Nooneb, M. Chris Runkenc, Deborah Gelinasc, and James W. Russelld,*

aDivision of Neurology, University of Toronto, 200 Elizabeth St, 5EC-309, TGH, Toronto, ON, M5G 2C4, Canada

bDepartment of Public Health Sciences, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA

cDepartment of Medical Affairs, Grifols, 79 TW Alexander Dr. Bldg 4101 Research Commons, Research Triangle Park, NC 27709, USA

dDepartment of Neurology, University of Maryland School of Medicine, and VA Maryland Health Care System, 110 S Paca Street, 3S-129, Baltimore, MD, 21201, USA

Abstract

Purpose—We reviewed the literature on chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetes mellitus (DM) and explored real-world data on the prevalence and treatment of

CIDP within DM. Methods: A literature search of Scopus was performed for the terms chronic inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, and prevalence, incidence, epidemiology, or diabetes; peripheral neuropathy and prevalence or diabetes. We also searched through the reference lists of the resulting publications for additional findings that may have been missed. Additional publications

on guidelines for the diagnosis of CIDP and diabetic neuropathy were also included. A descriptive

analysis of the 2009–2013 PharMetrics Plus™ Database was performed to estimate the prevalence

and treatment of CIDP within the DM population.

Results—There is an increasing body of literature suggesting that the prevalence of CIDP tends to be higher in diabetic patients, especially in those of older age. Our real-world data seem to

support published findings from the literature. For the total cohort (N = 101,321,694), the percent

prevalence of CIDP (n = 8,173) was 0.008%; DM (n = 4,026,740) was 4%. The percent prevalence

of CIDP without DM (n = 5,986) was 0.006%; CIDP with DM (n = 2,187) was 9-fold higher at

0.054%. For patients >50 years old, there was a significantly higher percentage of CIDP with DM

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). *Corresponding author at: Department of Neurology, University of Maryland School of Medicine, 110 S Paca Street, 3S-129, Baltimore, MD, 21201. Tel.: +1 410 328 3100; fax: +1 410 328 8981., Russell@som.umaryland.edu (J.W. Russell).

Conflict of Interest Disclosure: V.B. has received grant funding from Grifols, CSL Behring, and Alexion; has consulted for Grifols, CSL Behring, Alexion, and Bionevia; and has participated as a speaker on behalf of Grifols. D.G. and M.C.R. are employees of Grifols. C.M.B. and J.M.N. have received consulting fees from Grifols for this study. J.W.R. is supported in part by the Office of Research Development, Department of Veterans Affairs (Biomedical and Laboratory Research Service and Rehabilitation Research and Development, 101RX001030) and Baltimore GRECC. There are no other relevant conflicts of interest.

U.S. Department of Veterans Affairs Public Access Author manuscript J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

Published in final edited form as: J Diabetes Complications. 2016 ; 30(7): 1401–1407. doi:10.1016/j.jdiacomp.2016.05.007.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

http://creativecommons.org/licenses/by-nc-nd/4.0/
than CIDP without DM. Approximately 50% of CIDP patients were treated with IVIg, 23%–24%

with steroids, 1%–2% with PE, and 20%–23% received no treatment.

Conclusions—In addition to the growing evidence of higher prevalence of CIDP in DM, our findings reinforce the need for heightened awareness of the association of CIDP and DM.

Keywords

Chronic inflammatory demyelinating polyneuropathy; CIDP; Diabetes mellitus; Diabetic peripheral neuropathy; Prevalence; Diabetic peripheral neuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous,

progressive or relapsing–remitting, immune-mediated disorder of the peripheral nervous

system that has an estimated prevalence of 1–8.9 per 100,000 (Chio, Cocito, Bottacchi, et

al., 2007; Hafsteinsdottir, Olafsson, & Stefansson, 2012; Laughlin, Dyck, Melton, et al.,

2009; Lunn, Manji, Choudhary, et al., 1999; McLeod, Pollard, Macaskill, et al., 1999;

Mygland & Monstad, 2001; Rajabally, Simpson, Beri, et al., 2009). The epidemiology of

CIDP varies depending on the diagnostic criteria used (Rajabally, Simpson, et al., 2009).

CIDP has typical and atypical phenotypic variants (Mathey, Park, Hughes, et al., 2015).

Only half of CIDP patients have typical CIDP, which exhibits symmetrical sensory and

motor symptoms. The remainder has atypical disease, which presents with predominantly

focal, sensory, motor, distal or asymmetrical symptoms. Despite increased efforts to identify

a biomarker, there is no definitive diagnostic marker for CIDP, and recognition of CIDP is

not straightforward in some cases due to its heterogeneous nature (Jann, Bramerio, Beretta,

et al., 2003; Latov, 2011; Sommer & Toyka, 2011).

A thorough literature search of Scopus—an abstract and citation database of peer-reviewed

literature—was performed for all publications, including but not limited to case reports,

reviews, clinical studies, meeting abstracts, book chapters, for the terms chronic inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, and prevalence, incidence, epidemiology, or diabetes; peripheral neuropathy and prevalence or diabetes. We also searched through the reference lists of the resulting publications for additional findings that may have been missed. All publications

included were in the English language, and there was no limit on year of publication.

Additional publications on guidelines for the diagnosis of CIDP and diabetic neuropathy

were also included.

1. Diagnosis of CIDP

The diagnosis of CIDP is based on the recognition of clinical features, neurological

examination, and electrodiagnostic criteria. Electrodiagnostic studies include

electromyograms and nerve conduction studies (NCSs). Nerve conduction studies and

electrophysiological evidence of demyelination are required to confirm the diagnosis (AAN,

1991; EFNS/PNS, 2010; Krarup, 2003; Latov, 2014; Tesfaye, Boulton, Dyck, et al., 2010),

while laboratory testing, elevated protein levels in cerebrospinal fluid (CSF), and nerve

biopsy can help rule out other causes for neuropathy and support the diagnosis (EFNS/PNS,

2010; Koller, Kieseier, Jander, et al., 2005). As the disease progresses, electrophysiological

Bril et al. Page 2

J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

evidence of axonal damage may become superimposed on the demyelinating CIDP features

(Hughes, Allen, Makowska, et al., 2006). Patients with CIDP typically present with

progressive weakness in both proximal and distal muscles, areflexia, sensory symptoms with

proximal weakness, and preferential loss of sensation for vibration or joint position (EFNS/

PNS, 2010). Clinical observations of muscle weakness and loss of sensation are

manifestations of nerve demyelination that result in conduction blocks and delays in

conduction speed.

The 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/

PNS) guidelines are globally accepted for both clinical and research purposes (EFNS/PNS,

2010; French & Vallat, 2008; Koski, Baumgarten, Magder, et al., 2009; Rajabally, Fowle, &

Van den Bergh, 2015; Rajabally, Nicolas, Pieret, et al., 2009) due to their balance between

high sensitivity (73.2%) and specificity (90.8%) for CIDP (Breiner & Brannagan, 2014;

Rajabally, Simpson, et al., 2009; Rajabally et al., 2015). In contrast, the American Academy

of Neurology (AAN) criteria (AAN, 1991) can have a sensitivity as low as 3.6% and a

specificity of 100% for CIDP. The EFNS/PNS guidelines define CIDP as “definite,”

“probable,” or “possible” based on specifics surrounding motor distal latency prolongation,

reduction of motor conduction velocity, prolongation or absence of F-waves, motor

conduction block, and distal compound muscle action potential (CMAP) duration (EFNS/

PNS, 2010). Testing of multiple limbs is more sensitive than testing of unilateral or lower

limbs in optimizing electrodiagnostic testing for CIDP, particularly in atypical CIDP (Chin,

Deng, Bril, et al., 2015; Rajabally, Jacob, & Hbahbih, 2005; Vo, Hanineva, Chin, et al.,

2015). Additional tests that may be needed to support a diagnosis of CIDP are elevated CSF

protein with a leukocyte count less than 10/mm3, magnetic resonance imaging (MRI) of the

lumbosacral or cervical nerve roots or the brachial or lumbosacral plexuses, nerve biopsy,

and clinical improvement after immunomodulatory treatment (Abe, Terashima, Hoshino, et

al., 2015; EFNS/PNS, 2010; Midroni, de Tilly, Gray, et al., 1999). Newer techniques for

detecting proximal demyelination as well as treatment response include ultrasonography (Di

Pasquale, Morino, Loreti, et al., 2015; Guidon, 2015; Jang, Cho, Yang, et al., 2014;

Kerasnoudis, Pitarokoili, Behrendt, et al., 2014; Kerasnoudis, Pitarokoili, Behrendt, et al.,

2015; Kerasnoudis, Pitarokoili, Gold, et al., 2015), magnetic stimulation of the cauda equine

(Maccabee, Eberle, Stein, et al., 2011), somatosensory evoked potentials (Devic, Petiot, &

Mauguiere, 2015), MRI gadolinium enhancement of the spinal nerve roots (Midroni et al.,

1999), and magnetic resonance neurography with 3-dimensional reconstruction to determine

patterns of nerve hypertrophy and to differentiate the pathophysiology of CIDP subtypes

(Shibuya, Sugiyama, Ito, et al., 2015).

2. Diabetes mellitus and diabetic neuropathies

According to the Centers for Disease Control and Prevention, DM affects about 9.3% of the

general population in the United States in contrast to 25.9% in persons 65 years or older

(CDC, 2014). Type 2 DM (T2DM) results in insulin resistance and accounts for >90% of

cases (Handelsman, Mechanick, Blonde, et al., 2011; Russell & Zilliox, 2014). The

prevalence of T2DM increases with age, elevated body mass index, and family history

(Handelsman et al., 2011). Due to the gradual onset of T2DM, early symptoms often go

unrecognized (Russell & Zilliox, 2014). Some investigators report CIDP to be more frequent

Bril et al. Page 3

J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

in patients with T2DM (Dunnigan, Ebadi, Breiner, et al., 2013), while others report equal

occurrence of CIDP in type 1 DM and T2DM (Sharma, Cross, Ayyar, et al., 2002). While it

is estimated that 50% of patients with DM have some form of neuropathy, more than 80% of

these cases are diabetic peripheral neuropathy (DPN)—a length-dependent, sensory more

than motor, axonal neuropathy (Chin & Rubin, 2010). Early signs of DPN manifest through

distal loss of sensation in the feet and/or loss of deep tendon reflexes at the ankles. The risk

of developing DPN increases with the duration of DM and glycemic control, and DPN may

precede the formal diagnosis of DM by years (Chin & Rubin, 2010; Handelsman et al.,

2011; Russell & Zilliox, 2014).

3. Controversy: the association of CIDP and DM

In the 1975 seminal paper on CIDP (Dyck, Lais, Ohta, et al., 1975), Dr Peter J. Dyck stated,

“Patients with diabetes mellitus […] who had a neuropathy whose clinical,

neurophysiologic, and pathologic features were indistinguishable from the neuropathy

studied here, have not been included under this designation [of CIDP] even though it may be

shown eventually that pathogenetic mechanisms may be similar or alike.”

Forty years later, the association between CIDP and DM is still being debated. Diagnosing

CIDP in a patient with DM is more challenging, as superimposed axonal damage can

obscure electrophysiology findings of CIDP, and DPN can cause elevated CSF protein

(Gorson, Ropper, Adelman, et al., 2000). One study has reported that the occurrence of

CIDP is 11-fold higher in diabetic than nondiabetic patients; however, this was a smaller

nonpopulation based study (Sharma, Cross, Farronay, et al., 2002). Another study estimated

that CIDP occurs in 9% of patients with DM (Lozeron, Nahum, Lacroix, et al., 2002), while

others have reported that there is no association between CIDP and DM (Dyck, Engelstad,

Norell, et al., 2010; Laughlin et al., 2009). One publication stated that an overemphasis on

electrophysiological criteria may cause confusion in the perceived association between

CIDP and DM (Laughlin et al., 2009). However, that study was retrospective, had a small

CIDP population (only 19 patients met the Mayo Clinic clinical and electrophysiological

criteria for CIDP), was from a relatively limited patient demographic, and had only 1 patient

with both CIDP and DM. Moreover, full electrophysiological characteristics of subjects

were not reported. A subsequent report by the same authors investigated whether painless

diabetic motor neuropathy might represent CIDP (Garces-Sanchez, Laughlin, Dyck, et al.,

2011). Based on clinical presentation, electrophysiology, and a strong emphasis on sural

nerve biopsy, the authors concluded that painless diabetic motor neuropathy was a painless

form of diabetic lumbosacral radiculoplexus neuropathy, not CIDP.

Patients with both CIDP and DM tend to have extensive axonal loss with more severe

neuropathy yet may respond to treatment (Dunnigan, Ebadi, Breiner, et al., 2014; Gorson et

al., 2000). A small study comparing 14 patients with CIDP and DM to 60 patients with

CIDP alone, found that CIDP patients with DM were older (67 years vs. 49 years,

respectively) and had similar response rates to corticosteroids, intravenous immunoglobulin

(IVIg), plasma exchange (PE), and cyclophosphamide (Gorson et al., 2000). Patients with

CIDP and DM exhibited more severe axonal loss, likely the result of underlying diabetic

axonal polyneuropathy (Dunnigan et al., 2013). In contrast to patients with DPN (n = 56),

Bril et al. Page 4

J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

diabetic patients with CIDP (n = 67) had more extensive slowing of motor nerve conduction

velocity (32.4 ± 6.4 m/s vs. 35.2 ± 3.4 m/s, P = 0.006). Diabetic patients with CIDP also tended to be older (65.1 ± 13.7 years vs. 55 ± 16 years, P = 0.0003), have shorter duration of diabetes (16.5 ± 13.5 years vs. 24.0 ± 15.6 years, P = 0.005), have more severe neuropathy (ie, higher Toronto Clinical Neuropathy Score, higher vibration perception threshold, and

more weakness), and have better glycemic control compared with diabetic patients who did

not have CIDP but had slowed conduction velocities (HbA1c 7.7 ± 2.0% vs. 9.6 ± 2.4%, P = 0.003).

EFNS criteria are less predictive of treatment response in CIDP patients with DM (Abraham,

Breiner, Katzberg, et al., 2015). CIDP patients with DM were more likely to respond to

treatment if they fulfilled 2 EFNS/PNS electrophysiological criteria whereas CIDP patients

without diabetes were likely to respond with only 1 criterion met (Table 1). In diabetics,

fulfilling more diagnostic criteria for CIDP (more evidence of demyelinating neuropathy on

NCSs) was associated with higher response rates to treatment (Cocito, Chio, Tavella, et al.,

2006). The recent retrospective study (Dunnigan et al., 2014) also demonstrated that patients

with CIDP and DM were less likely to be treated even though they had similar response

rates to treatment as CIDP patients without DM and higher rates of proximal weakness and

ataxia (Table 2).

4. Real-world data analysis of health insurance administrative claims

4.1. Methods

4.1.1. Database description—Controversies on the overlap of CIDP within DM led us to investigate the prevalence of CIDP and DM in a “real-world” health insurance

administrative claims database—the 2009–2013 Phar-Metrics Plus™Database (Watertown,

MA, USA). Secondary objectives were to determine any impact of age on the diagnosis of

CIDP patients both without and with DM and to highlight any differences in treatment

patterns. This database represents a pooling of adjudicated medical and pharmacy claims for

over 100 million patient lives from more than 90 different health plans across the United

States. The database includes inpatient and outpatient diagnoses in International

Classification of Diseases-9th Revision-Clinical Modification (ICD-9-CM) format;

procedures in Current Procedural Terminology-4th Edition and the Healthcare Common

Procedure Coding System; and prescription records (Blanchette, Roberts, Petersen, et al.,

2011). It also includes demographic variables, product and insurance type, provider

specialty, and dates inclusive of plan enrollment. This private database includes a limited

number of patients enrolled in Medicaid or Medicare and, therefore, underrepresents the

patient population older than 65 years. A typical limitation of any claims database analysis is

that clinical data are unavailable for the diagnostic criteria by which the diagnoses of CIDP

and DM were made. To ensure the robustness of this dataset, we applied stringent inclusion

criteria. Patients were confirmed with DM if there were ≥2 claims based on ICD-9-CM code

250. For a CIDP confirmation, patients were required to have ≥2 CIDP claims (ICD-9-CM

code 357.81) reported at least 90 days apart. Incident cases were defined as being free of a

CIDP diagnosis during the 12-month baseline period before their index date.

Bril et al. Page 5

J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

4.1.2. Statistical analysis—Descriptive statistics were used to assess differences in the population. Chi-square tests were used to assess differences in age distributions between

CIDP patients without and with DM. Statistical significance was set at an alpha level of

0.05. This study was exempt from any institutional review board review because the patient

information within the database was de-identified.

4.2. Results of database analysis

In this retrospective database study (N = 101,321,694), the prevalence of patients with CIDP

(n = 8,173) was 8 per 100,000 persons (0.008%), which was similar to a previously reported

prevalence value of 8.9 per 100,000 persons (Laughlin et al., 2009). Reflective of the

generally younger patient population in the database, the overall prevalence of patients with

DM (n = 4,026,740) was 3,974 per 100,000 persons (4.0%), which was lower than the 9.3%

reported in the general United States population (CDC, 2014). However, in the population

older than 55 years (n = 2,461,140), the percent prevalence of patients with DM was 11,567

per 100,000 persons (11.6%). The prevalence of CIDP among nondiabetic patients (n =

5,986) was 6 per 100,000 persons (0.006%). In contrast, the prevalence of CIDP in the

diabetic population (n = 2,187) was 9-fold higher at 54 per 100,000 persons (0.054%). In

this claims database study, clinical data are not available, and the accuracy of the diagnoses

for DM and CIDP cannot be confirmed; yet the relative risk of having both CIDP and DM at

9-fold higher than having CIDP alone is approaching the 11-fold increase previously

reported by Sharma et al., using the highly specific AAN criteria (Sharma, Cross, et al.,

2002).

To improve the stringency around the CIDP diagnosis in this epidemiological cohort, we

mandated that confirmed CIDP cases have distinct ICD-9-CM codes reported at least 90

days apart. A total of 2,048 patients had confirmed CIDP with ≥12 months pre- and post-

index periods and ICD-9-CM codes of at least 90 days apart. Within this confirmed CIDP

group, 1,411 (69%) patients had CIDP without DM, and 637 (31%) patients had CIDP with

DM. These data were similar to the 25.7% of patients who had clinically confirmed CIDP

with DM in another database study (Kalita, Misra, & Yadav, 2007). In our current study, the

median ± standard deviation (SD) age was 56.4 ± 14.5 years for CIDP without DM and 61.6

± 11.8 years for CIDP with DM. In patients aged 50 years or younger, CIDP without DM

was more common than CIDP with DM (P < 0.01) (Fig. 1), suggesting that misdiagnosis of CIDP was not likely in this dataset. No difference in prevalence rates was found in patients

aged 51 to 60 years in both groups (29.98% CIDP without DM vs. 31.08% CIDP with DM,

P = 0.61). In those aged 61 to 70 years, there was a trend for CIDP with DM to be more common than CIDP without DM, but statistical significance was not reached (33.28% CIDP

without DM vs. 29.34% CIDP with DM, P = 0.07). Despite the relatively smaller number of patients in the 2 highest age groups, the percentage of patients aged ≥71 years with CIDP

and DM was statistically significantly higher than those without DM (P < 0.01). In addition, the treatment of CIDP patients without or with a concomitant diagnosis of DM was found to

be similar. Approximately 50% of patients were treated with IVIg (57% CIDP without DM

and 52% CIDP with DM), 23%–24% with steroids, 1%–2% with PE; and approximately

20%–23% received no treatment in both groups (Fig. 2). Although clinical data are not

available, one might hypothesize that these untreated patients had only mild disability and

Bril et al. Page 6

J Diabetes Complications. Author manuscript; available in PMC 2017 July 26.

V A

A u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t V

A A

u th

o r M

a n u scrip

t

therefore, according to EFNS/PNS guidelines, would be managed with monitoring for

disease worsening (EFNS/PNS, 2010). Notably, steroid and IVIg use was similar between

both groups. As only claim data were available, we cannot comment on the responsiveness

of these patients to various treatments.

In an alternative analysis evaluating this database with less stringent inclusion criteria (ie, ≥2

CIDP claims reported at no particular time interval), the reliability of this dataset became

more evident. Without requiring the CIDP claims to be reported at least 90 days apart, we

found similar results to those derived from the more stringent analysis previously described.

A total of 3,399 patients had confirmed CIDP; 2,380 (70%) patients had CIDP without DM;

and 1,019 (30%) patients had CIDP with DM. Comparable to the data described in Fig. 1,

the age distribution derived from this less stringent analysis demonstrated: (A) CIDP without

DM was more common than CIDP with DM (P = 0.01) in patients aged <50 years; (B) there was no difference in patients aged 51 to 60 years for both groups (29% CIDP without DM

and 30% CIDP with DM, P = 0.36); however, (C) CIDP with DM was statistically significantly higher than CIDP without DM in patients aged >61 years (P = 0.01). Treatment of CIDP patients without or with a concomitant diagnosis of DM also appeared consistent

with data described in Fig. 2 (approximately 40% of patients were treated with IVIg, 27%

with steroids, 1%–2% with PE, and roughly 30% received no treatment).

Interestingly, the CIDP patient age distribution in this large United States database was

similar to the age distribution observed in an Italian epidemiological study (N = 4,334,225),

in which older patients had a higher prevalence of CIDP than younger patients (Chio et al.,

2007). We, thus, conclude that diabetes may be a common comorbidity along with CIDP in

patients older than 50 years. Despite the potential selection bias for fewer patients older than

65 years (due to a limited number of patients ≥65 years old enrolled in Medicare), we expect

that such bias would not only underestimate the prevalence of DM observed, but also

underestimate the associated prevalence of patients with CIDP and DM.

5. Treatment of CIDP with DM

At present, the decision on how to treat CIDP with DM is guided by treatment for CIDP

without DM. CIDP is the most common treatable autoimmune neuropathy (Mathey et al.,

2015); up to 80% of patients with CIDP respond to treatment. Clinical studies have shown

that corticosteroids, PE, and IVIg all have efficacy in CIDP (Dyck, Daube, O’Brien, et al.,

1986; Dyck, O’Brien, Oviatt, et al., 1982; Hahn, Bolton, Pillay, et al., 1996a; Hughes,

Donofrio, Bril, et al., 2008; Mehndiratta & Hughes, 2002; Rajabally, 2015). The EFNS/PNS

guidelines (EFNS/PNS, 2010) recommend IVIg or corticosteroids for sensory and motor

CIDP; IVIg for pure motor CIDP; and if IVIg and corticosteroids are both ineffective, PE

should be considered. Combination treatment or the addition of an immunosuppressant or

immunomodulatory drug may be considered if the response to IVIg, corticosteroids, or PE is

inadequate. Several clinical studies have shown that patients with CIDP and DM are also

responsive to immunological treatment (Cocito, Ciaramitaro, Isoardo, et al., 2002; Dunnigan

et al., 2014; Gorson et al., 2000; Jann, Bramerio, Facchetti, et al., 2009; Krendel, Costigan,

& Hopkins, 1995; Sharma, Cross, et al., 2002a; Stewart, McKelvey, Durcan, et al., 1996).

Treatment decisions depend on factors such as concomitant diseases, cost, therapeutic