THERAPEUTIC PLASMA EXCHANGE AND DOUBLE FILTRATION PLASMAPHERESIS IN SEVERE NEUROIMMUNE DISORDERS.

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique, which removes large molecular weight particles such as autoantibodies from plasma. TPE is accepted by the American Society for Apheresis as first line treatment for some severe neuroimmune disorders. Double filtration plasmapheresis (DFPP) is a newer technique in which plasma is not entirely removed, only the antibodies, using special filters. High-dose intravenous immunoglobulins are an alternative treatment for these patients but are much more expensive. We reviewed medical records of 20 patients with severe neurological diseases requiring TPE or DFPP. We analyzed the indications, complications and efficacy of these procedures. After completing the procedures, neurological improvement was recorded in 80% of the patients, 5% had no improvement, and the mortality was 15%. The rate of neurological improvement was similar to other studies. None of the patients presented catheter related complications. Systemic complications were mild, transient and completely reversible.

Introduction

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique designed to remove large molecular weight particles from plasma. The principal mechanism of action consists of removing circulating autoantibodies, immune complexes, cytokines, monoclonal proteins, toxins and other inflammatory mediators ().This procedure is clinically available from the early 1970s for the treatment of several neuroimmune disorders (). Removing these pathogenic substances from patient plasma, in recent years this procedure has been increasingly indicated for hematologic, neurological, connective tissue, nephrologic and metabolic disorders (). Double filtration plasmapheresis (DFPP) is a newer technique in which plasma is not entirely removed, only the antibodies, using special filters. Recent reports claim TPE to have numerous immunomodulatory effects (). Plasmapheresis is accepted as first line treatment, according to the American Society for Apheresis (ASFA) 2013 guidelines (), for the following neuroimmune disorders: Guillain-Barré syndrome (GBS), myasthenia gravis in severe crisis, chronic inflammatory demyelinating polyneuropathy and fulminant forms of Wilson disease. Plasmapheresis is accepted as second line therapy in Lambert-Eaton myasthenic syndrome, multiple sclerosis relapsing-remitting form, acute disseminated encephalomyelitis (ADEM) and in neuromyelitis optica (NMO) unresponsive to high-dose corticosteroids.

High-dose intravenous immunoglobulins (IVIG) represent an alternative treatment for severe neuroimmune disorders. According to ASFA guidelines, the efficiency is equal for both treatments (). Many physicians prefer IVIG because administration is easy, safe and involves few complications (, ), but IVIG is very expensive and is not covered by governmental health insurance in many countries (, ).

Materials and Methods

We retrospectively reviewed medical records of 20 patients with severe autoimmune neurological diseases requiring TPE or DFPP, treated in our hospital during a 4-year period (from November 2012 to December 2016). We analyzed the indications, side effects, complications and efficacy of those procedures in these patients. The study was approved by the Ethics Board of the County University Emergency Hospital Sibiu (SCJU Sibiu). All patients signed an informed consent form prior to the procedure (after the procedural risks being explained in detail by a senior physician).

The patients were admitted to the Intensive Care Unit (ICU) until the procedures were over. The right internal jugular vein was catheterized with a 20 F double lumen catheter in 18 patients and the left internal jugular vein was catheterized with a 20 F double lumen catheter in two patients. This procedure was performed under local anesthesia, with an aseptic technique. X-ray control was performed to assure proper position of the catheter.

To remove autoantibodies, we used 2 techniques, TPE and DFPP, using the HF440 machine (Infomed SA, Geneva, Switzerland) for both. Cascade filtration is a 2-step process during which plasma is first extracted from the blood and then circulated through a second filter, plasma fractionator. Having a membrane pore size approximately 10-fold smaller than a plasmafilter, the plasma fractionator retains larger molecules such as immunoglobulin G (IgG), low-density lipoprotein (LDL)-cholesterol and viruses. The plasma is filtered and then returned to the patient, thus avoiding or minimizing the need for replacement fluids. The process can be named double filtration or DFPP (Double Filtration PlasmaPheresis).

The extracted plasma volume was calculated individually, using Nadler’s formula and hematocrit, in a range of 1.5 total plasma volume/session. For TPE, we used a Granopen 060 Plasmafilter (Infomed SA, Geneva, Switzerland). As volume replacement fluids, we used a mixture of fresh frozen plasma (FFP) 800-900 mL, hydroxy ethyl starch (HES) 6% solution 1000 mL and 4% solution of human albumin (20% solution diluted in saline) to make up to the desired volume. DFPP was performed using a Granopen 060 Plasmafilter and Medopen 30 Plasmaseparator (Infomed SA, Geneva, Switzerland), with no necessity of replacement fluids. A session was usually performed within 2.5 to 6 hours depending on blood flow through the machine and plasma exchange rate, and repeated every 24-48 hours depending on the neurological status.

Results and Discussion

Twenty patients were included in the study and a total of 62 TPE procedures and 14 DFPP sessions were performed (Table 1). Of these 20 patients, 11 (55%) were women and nine (45%) were men, median age 56 (range 13-85) years, with the following diagnoses: GBS in nine (45%), myasthenia gravis (MG) in four (20%) patients, neuromyelitis optica (NO) in one (5%) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in one (5%) patient. The remaining 25% of patients had the following diagnoses: stiff-man syndrome, transverse myelitis, progressive form of multiple sclerosis, NMO spectrum disorders and West-Nile encephalitis in one patient each.

Table 1

Number of TPE and DFPP sessions according to patient diagnoses

Diagnosis	GBS (n=9)	CIDP (n=1)	MG (n=4)	NMO (n=1)	Other (n=5)	Total (N=20)
Age (median)	59	57	54	58	48	56
Sex (F/M)	3/6	1/0	2/2	1/0	4/1	11/9
TPE as first-line therapy (n)	8	-	1	-	1	10
TPE as second-line therapy (n)	1	1	2	1	4	9
Total TPE sessions (n)	30	3	11	4	14	62
DFPP as first-line therapy (n)	1	-	-	1	-	2
DFPP as second-line therapy (n)	2	-	1	-	1	4
Total DFPP sessions (n)	7	-	3	1	3	14
TPE session/patient (mean)	4	3	3.5	4	4	3,8
DFPP session/patient (mean)	3	-	3	2	2	2.5

TPE = therapeutic plasma exchange; DFFP = double filtration plasmapheresis; GBS = Guillain-Barre syndrome; CIDP = chronic inflammatory demyelinating polyneuropathy; MG = myasthenia gravis; NMO = neuromyelitis optica; FFP = fresh frozen plasma

Ten (50%) of the 20 patients were treated with TPE and three (15%) with DFPP as first-line therapy, whereas nine (45%) patients received TPE and four (20%) received DFPP as second-line therapy. The mean number of TPE sessions/patient and DFPP sessions/patient was 3.8 (range 3-4) and 2.5 (range 2-3), respectively. For TPE, a total of 219 human albumin 20% solution vials and 274 bags of FFP were used as replacement fluids. Eight patients having benefited from TPE and DFPP sessions received steroid medication before plasma exchange (three patients with MG and one patient with CIDP, multiple sclerosis, stiff-man syndrome, NMO and NMO spectrum disorders each). Other therapies (IVIG or immunosuppressive medication) were not used before administration of plasma exchange therapy (Table 2).

Table 2

Use of steroid therapy, IVIG and replacement fluids according to patient diagnoses

Diagnosis	GBS (n=9)	CIDP (n=1)	MG (n=4)	NMO (n=1)	Other (n=5)	Total (N=20)
Responsive to treatment (n)	8	1	3	1	3	16
Steroid	0	1	3	1	3	8
IVIG	-	-	-	-	-	-
Replacement fluid (vials, n)
Albumin	100	6	57	13	43	219
FFP	143	14	47	18	52	274

IVIG = intravenous immunoglobulin; FFP = fresh frozen plasma; GBS = Guillain-Barre syndrome; CIDP = chronic inflammatory demyelinating polyneuropathy; MG = myasthenia gravis; NMO = neuromyelitis optica

A total of 25 systemic complications associated with TPE and DFPP were recorded (Table 3). There were no local complications related to the central venous catheter. The most common systemic complications of plasma exchange were hypocalcemia in nine (36%), hyponatremia in four (16%) and hypokalemia in five (20%) patients. These patients presented perioral and limb paresthesias and muscle cramps; these were mild and transient and never required interruption of the plasma exchange session. Mild, transient hypotension (systolic blood pressure <100 mm Hg) occurred in two (8%) patients, with minimal or no symptoms. Infection/sepsis (generated by prolonged immobilization) developed in five (20%) patients. The complication rate was 32% in the total of 76 TPE and DFPP sessions.

Table 3

Complications according to patient diagnoses

Diagnosis	GBS (n=9)	CIDP (n=1)	MG (n=4)	NMO (n=1)	Other (n=5)	Total (N=20)
Catheter related	-	-	-	-	-	-
Hypocalcemia	5	-	2	1	1	9
Hyponatremia	2	1	1	-	-	4
Hypokalemia	3	-	2	-	-	5
Hypotension	1	-	-	-	1	2
Infections/sepsisTotal complications	213	-1	27	-1	13	525
Death	1	-	1	-	1	3

GBS = Guillain-Barre syndrome; CIDP = chronic inflammatory demyelinating polyneuropathy; MG = myasthenia gravis; NMO = neuromyelitis optica

No patient death was recorded during the plasma exchange procedures. Three patients died from septic shock secondary to bronchopneumonia, including one patient with GBS, West-Nile encephalitis and MG (aspiration pneumonia) each, late in the evolution of the disease (Table 3).

After completing the plasma exchange sessions, 80% of the patients had clinical neurological improvement, 5% had no improvement, and the mortality was 15%.

Guillain-Barré syndrome is a major cause of acute generalized paralysis; 5% of patients with severe evolution develop respiratory failure that requires endotracheal intubation and mechanical ventilation (). The primary pathogenesis is a presumed autoimmune attack on peripheral nerves (). In our study, we included nine patients with GBS with the following etiology: flu vaccine in one patient, enterocolitis in two patients and respiratory infections in six patients. International guidelines suggest TPE or IVIG as front line treatment for severe GBS (). On the one hand, the efficiency of TPE and IVIG in GBS (both being equally efficient) has been underlined by two Cochrane reviews (, ). On the other hand, IVIG treatment has proven to be twice as expensive in comparison with TPE, with similar clinical response (). A recent study published by Kumar et al. presents a group of 17 patients with GBS, each of them receiving TPE, 82.35% of these having a positive clinical outcome (). In another study reported by Hahn et al., the TPE procedure was applied to 15 patients with GBS and 12 (80%) had good outcome (). In our study, we had nine patients with GBS, and eight (88.8%) of them showed significant improvement after TPE, similar to the studies mentioned above.

Myasthenia gravis is another neuroimmune disorder, in which 15% to 20% of patients evolve with myasthenic crises (MC) (, ). MC is defined as acute respiratory failure or bulbar weakness causing dysphagia, with a high risk of aspiration, requiring tracheal intubation at ICU (). Literature reports claim that TPE and IVIG are both equally efficient in MC (). Kumar et al. report on a success rate of TPE in 11 (84.6%) of 13 patients with MC (). In our group, there were four patients with MC, and three of them successfully recovered after TPE. Some studies support DFPP in treating MC (). In our group, one patient with MC was successfully treated with 3 DFPP sessions, applied every other day.

The patients with RRMS and NMO had a 5-year evolution of the disease with slight response to corticosteroids and multiple relapses. Among the autoantibodies that play a role in MS pathogenesis, most important are proteins involved in the composition of myelin sheath, i.e. myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin proteolipid protein (PLP) and myelin-associated protein (MAG), this being the reason why the ASFA 2013 guidelines recommend plasmapheresis as second-line therapy (). As far as NMO is concerned, the relapse treatment is IV methylprednisolone, and if it fails to improve the neurological status, plasma exchange must be considered. New studies even suggest combining IV methylprednisolone with plasma exchange in patients with severe disease (). The patient with myelitis was newly diagnosed and we decided to perform TPE due to the fact that his symptomatology did not respond to corticotherapy.

Kaynar et al. report on a study involving 57 patients with neurological disorders that received an average of 5 TPE, with general improvement in 82% of patients (). In our group of 20 patients, improvement was recorded in 80% of patients. They received a mean of 3.8 TPE sessions, every other day.

In the above studies, the complications of TPE and DFPP were either local (related to venous catheter) or systemic (related to the TPE or DFPP procedure). In our study group, none of the patients developed catheter related complications, while systemic complications were mild, transient and completely reversible, and did not require interruption of the procedure. Some patients complained of paresthesias and cramps due to electrolyte imbalances. According to the World Apheresis Registry Data 2003-2007, the incidence of these symptoms is 1.5%-9% ().

Conclusions

The TPE and DFPP procedures provide first-line management in several neuroimmune disorders with severe evolution. In our study, the overall neurological improvement rate after TPE and DFPP procedures was 80%, with mild and manageable complications and without death generated directly by these procedures. The alternative treatment to TPE and DFPP is high-dose IVIG, which is easy to administer but is more expensive and difficult to obtain in our hospital. To our knowledge, this report presents the largest study group in our country in which neurological patients were treated with TPE and DFPP. These therapeutic procedures are safe and efficient, provided that they are performed by experienced practitioners, and are much less expensive than IVIG while having the same efficiency.