Abstract
Background: Activated macrophages and T lymphocytes may play a role in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). Both cell types secrete tumor necrosis factor-α (TNFα), which has toxic effects on myelin and endothelial cells.
Methods: The serum concentration of TNFα was measured by ELISA and compared with clinical and electrophysiological profiles in 20 patients with CIDP.
Results: An increased serum level of TNFα was detected in 5 (25%) patients and was associated with subacute progression, severe neurologic disabilities, and symmetric weakness involving proximal as well as distal muscles. TNFα levels increased during the active phase in this subgroup of patients. The levels of TNFα correlated with the severity of demyelinating conduction abnormalities in the intermediate as well as distal nerve segments, suggesting demyelination diffusely distributed along the nerves.
Conclusion: Circulating TNFα increases during the active phase in a subgroup of CIDP patients and may play a role in the pathogenesis of demyelination and the breakdown of the blood–nerve barrier in CIDP.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a demyelinating disease of the peripheral nerves in which myelin is presumably the target of the immune attack.1 During the active phase of CIDP, nerve biopsies often show endoneural inflammatory changes with T-cell infiltration and macrophage-associated demyelination.2 Both T cells and macrophages secrete tumor necrosis factor-α (TNFα), a pro-inflammatory cytokine that has toxic effects on myelin, Schwann cells, and endothelial cells.3
Increased serum TNFα concentration has been reported in patients with Guillain–Barré syndrome.4-7⇓⇓⇓ The observed levels correlated with clinical and electrophysiological severity.4,7⇓ Moreover, TNFα levels have been shown to return to normal in parallel with clinical recovery, suggesting that TNFα plays a role in the pathogenesis of the demyelinating form of Guillain–Barré syndrome.7 On the other hand, increased serum TNFα concentrations have never been observed in patients with CIDP.4,7-10⇓⇓⇓⇓ It is likely that CIDP is a heterogeneous disorder,11 having a clinical spectrum ranging from subacute12 to chronic progression and a monophasic to relapsing course.11-13⇓⇓ In addition, it can include predominantly proximal to distal weakness1,14⇓ and may involve a range of neuropathy from symmetric polyneuropathy to mononeuropathy multiplex.15 Serum TNFα levels can increase in a certain subtype of CIDP. It is also possible that serum levels increase at a particular clinical stage during longer-term courses. We therefore measured serum TNFα concentration in patients with CIDP and compared the results with the corresponding clinical profiles and electrophysiological abnormalities.
Methods.
Patients.
Twenty patients at Chiba University Hospital between 1991 and 1999 were included in the study. We excluded patients with multifocal motor neuropathy because their clinical, electrophysiologic, and immunologic features may be different from those of CIDP. Serum samples were available from each patient, and each participating subject had a condition that fulfilled the research criteria for CIDP of the American Academy of Neurology.16 Serum samples were collected in the initial progressive (n = 13) or relapsing (n = 7) phase and were stored at −80 °C until use. At the time the serum was obtained, the seven patients with relapse had received no treatment with corticosteroids, plasmapheresis, or intravenous immunoglobulin for 3 to 7 months. Sera from six patients were obtained sequentially before and after immunotherapy.
Clinical disabilities were evaluated with the Hughes functional grading scale (Grade 1: minor symptoms and signs, able to run; Grade 2: able to walk 5 meters without aids; Grade 3: able to walk 5 meters with aids; Grade 4: chair- or bed-bound). Motor nerve conduction studies including F-wave studies were performed using the conventional procedures in the median, ulnar, tibial, and peroneal nerves.
Serum TNFα assays.
Levels of serum TNFα were determined by an immunoassay (AN'ALYZA, human TNFα; Genzyme Techne, Minneapolis, MN). The test serum was added to the well of an ELISA plate that had been preincubated with monoclonal antibody to recombinant human TNFα. A standard curve was run on each assay plate using recombinant human TNFα in serial dilutions. If concentrations were below 4.4 pg/mL, the values were replaced by 4.4 pg/mL because the minimum detectable dose of TNFα in this assay was <4.4 pg/mL. Concentrations were regarded as elevated if they were higher than 3 SD above the mean value of 49 normal control samples. For statistical analysis, differences of median values were tested with the Mann–Whitney U test, using Stat View (version 4.5) software.
Results.
Clinical profiles.
The clinical features of 20 CIDP patients are shown in the table. All patients had chronic sensory and motor neuropathy that had been evolving for >3 months. Fourteen (70%) of the patients had symmetric polyneuropathy, and the remaining six had asymmetric polyneuropathy involving all four limbs. Most of the patients did not have cranial nerve involvement, except that two patients had ocular motor or facial nerve palsy. All 20 patients had sensory loss in all four limbs and generalized areflexia. Two patients had monoclonal gammopathy, whereas none had anti-myelin-associated glycoprotein or anti-ganglioside GM1 antibodies.
Clinical features of 20 patients with chronic inflammatory demyelinating polyneuropathy (CIDP)
Serum TNFα levels.
In 49 normal subjects, the mean ± SD serum TNFα concentration was 8.8 ± 5.7 pg/mL. The cutoff value (mean ± 3 SD of normal samples) was therefore set to 25.9 pg/mL. Elevated serum levels of TNFα were detected in five (25%) patients ( figure 1). Their mean ± SD value was 59.6 ± 22.0 pg/mL (range 41.6 to 90.5 pg/mL).
Figure 1. Serum concentration of tumor necrosis factor-α (TNFα) in healthy control subjects (n = 49) and patients with chronic inflammatory demyelinating polyneuropathy (CIDP; n = 20). The dashed line represents 3 SD above the mean value of normal controls.
Clinical features of patients with elevated levels of serum TNFα.
Of the five patients with raised TNFα levels, four patients were in their initial progressive phase and the remaining one had a relapse 4 months after intravenous immunoglobulin therapy. All five patients had symmetric, predominantly motor polyneuropathy involving proximal as well as distal muscles. At the time the serum was tested, none of the five patients could walk independently (table), and these patients had a higher Hughes grade than those who did not have elevated TNFα level (mean [range]: 3.8 [3 to 4] versus 2.7 [2 to 4]; p = 0.002). The initial course of disease was subacutely progressive; all five patients had become unable to walk within 3 months of disease onset or relapse. Three of them subsequently had a remitting–relapsing course; their condition responded well to plasmapheresis or intravenous immunoglobulin, but they experienced a treatment-dependent relapse during the follow-up period (2 to 9 years). The remaining two patients experienced a monophasic course; remission after corticosteroid treatment persisted for 3 and 6 years after the cessation of treatment.
Correlation of TNFα with clinical features is shown in figure 2. High concentrations of TNFα levels were associated with severe neurologic disability, symmetric symptoms, and a relapsing course. Two of the five patients with raised TNFα concentrations had sequential measurement of serum TNFα concentration before and after treatment. Serial measurement showed that the serum levels decreased and returned to the normal range 3 to 4 months after the initiation of treatment with plasmapheresis or immunoglobulin therapy.
Figure 2. Correlation between serum tumor necrosis factor-α (TNFα) levels and clinical profiles in 20 patients with chronic inflammatory demyelinating polyneuropathy. Values are expressed as means ± SEM.
Correlation of TNFα with electrodiagnostic parameters.
As a group, patients with elevated TNFα concentrations had significantly abnormal electrodiagnostic features consistent with nerve demyelination as compared with patients with undetectable levels of TNFα. A high concentration of TNFα was associated with significantly longer distal latencies and slower conduction velocities in median, ulnar, and tibial nerve studies ( figure 3). Peroneal nerve studies were not analyzed because compound muscle action potentials were not recordable in 6 of the 20 patients. Figure 4 illustrates the results of analysis of serially increasing serum TNFα concentrations and electrodiagnostic abnormalities in a patient with CIDP in whom the levels of TNFα correlated with the severity of nerve conduction abnormalities.
Figure 3. Motor nerve conduction according to the presence of tumor necrosis factor-α. Data are shown as means ± SD for patients with increased concentration (filled columns) and for patients without it (open columns).
Figure 4. Serial measurements of serum tumor necrosis factor-α (TNFα) levels in a single patient with chronic inflammatory demyelinating polyneuropathy. The high levels are associated with slowed motor nerve conduction velocity (MNCV) and a low amplitude of distally evoked compound muscle action potential (CMAP-amp) of the median nerve. IVIg = intravenous immunoglobulin; PP = plasmapheresis.
Discussion.
The current study is the first report of the presence of increased serum levels of TNFα in patients with CIDP. The frequency of raised serum TNFα concentration was not as high (25%) as that reported in cases of Guillain–Barré syndrome (27 to 63%).4-7⇓⇓⇓ However, the fact that the TNFα levels correlated with clinical severity (figure 2) and electrophysiological abnormalities (figure 3) and decreased after immunotherapy supports that the serum TNFα could reflect disease activity. This study showed that serum TNFα increases only in the active phase in a certain subgroup of severely affected patients, and this may explain negative results obtained in previous studies.4,8-10⇓⇓⇓
It remains unclear whether TNFα is directly involved in the pathogenesis of CIDP or if it is merely the result of activation of the immune system. However, TNFα can cause selective cytotoxic damage to human Schwann cells and myelinated fibers.3,17-19⇓⇓⇓ In addition, TNFα could result in increasing vascular permeability17,20,21⇓⇓ and breakdown of the blood–brain barrier18 and blood–nerve barrier.17 Impairment of the blood–nerve barrier may be important in the pathogenesis of CIDP, and a biopsy study has shown that infiltration by macrophages, which are the main source of TNFα, is often perivascular.2 Our results suggest that levels of TNFα are associated with disease severity, and this further supports that TNFα may be relevant to peripheral nerve demyelination in CIDP, although myelin damage in CIDP could be due to multiple factors involving humoral and cellular mechanisms, complements, and other cytokines.
High concentrations of TNFα were associated with symmetric motor-dominant polyneuropathy involving proximal as well as distal muscles, severe clinical disabilities, and subacute progression. Patients with high serum TNFα levels had electrophysiological evidence of demyelination diffusely distributed along the nerves. It is likely that circulating factors such as immunoglobulin, cytokines, and complements preferentially affect distal nerve terminals as well as the nerve roots where the blood–nerve barrier is anatomically deficient.22 However, breakdown of the blood–nerve barrier is necessary to develop demyelination in the intermediate nerve segments. TNFα may play a role in the disruption of this barrier and may lead to more severe disease.
Conversely, concentrations of TNFα did not increase in patients with asymmetric neuropathy and a chronic steady course. These features are similar to those of multifocal demyelinating neuropathy with persistent conduction block15 and of multifocal motor neuropathy.23 Both disorders are characterized by focal motor conduction block in the intermediate nerve segments.24,25⇓ Even if there is no increase in serum TNFα, a local cytokine increase cannot be ruled out; cellular responses and local endoneural cytokine release might occur in this subtype of CIDP.
The clinical pictures of CIDP vary and are heterogenous in course, distribution of lesion, and response to immunotherapies.11 Moreover, heterogeneity may be explained by differences in underlying pathogenesis. Circulating TNFα may reflect disease activity and may play an important role in the pathogenesis of this subgroup of patients with CIDP.
- Received September 7, 2000.
- Accepted November 8, 2000.
References
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Alert Me
Recommended articles
Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies
The diagnostic value of sural nerve T cells in chronic inflammatory demyelinating polyneuropathy
Electrophysiologic findings in multifocal motor neuropathy
Clinical Reasoning: A patient with rapidly progressive sensory loss and imbalance