Inflammatory Demyelinating Polyneuropathy Research Articles

Inflammatory demyelinating polyneuropathy after the ChAdOx1 nCoV-19 vaccine may follow a chronic course

BackgroundRare autoimmune neurological events have been reported during the ongoing global drive for mass vaccination as a means of controlling the Covid-19 pandemic. Guillain-Barré syndrome, an acute inflammatory neuropathy well recognised as a rare complication of influenza vaccination, has been reported to follow administration of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. MethodsWe report four patients with inflammatory demyelinating polyneuropathy after vaccination in whom a relapsing or progressive course indicated the development of chronic inflammatory demyelinating polyneuropathy (CIDP). ConclusionsAwareness of this complication and distinction from Guillain-Barré syndrome enables the timely institution of maintenance immunomodulatory treatment. Our report also highlights the likely relationship between vaccination and the subsequent development of CIDP, but definitive demonstration of a causal link needs larger studies.

Efgartigimod alfa. Neonatal Fc receptor (FcRn) antagonist, Treatment of generalized myasthenia gravis, Treatment of primary immune thrombocytopenia, Treatment of pemphigus vulgaris and foliaceous, Treatment of chronic inflammatory demyelinating polyneuropathy

Efgartigimod alfa. Neonatal Fc receptor (FcRn) antagonist, Treatment of generalized myasthenia gravis, Treatment of primary immune thrombocytopenia, Treatment of pemphigus vulgaris and foliaceous, Treatment of chronic inflammatory demyelinating polyneuropathy

T30. Sural nerve conduction studies in differentiation of hereditary and inflammatory demyelinating polyneuropathies

Introduction Nerve Conduction Studies (NCS) are invaluable tools for diagnosis and classification of polyneuropathies. However, differentiation of different types of demyelinating polyneuropathies may sometimes be difficult. Detection of demyelination and differentiation of inflammatory and hereditary polyneuropathies are mainly based on motor NCS. We aimed in this study to examine the role of sural nerve sensory NCS in differentiation of inflammatory and hereditary polyneuropathies. Methods Nineteen patients with chronic demyelinating polyneuropathy (CIDP), 16 patients with Guillain Barre syndrome (GBS) and 23 patients with hereditary motor sensory neuropathy with PMP22 duplication were included. In all patients, sural nerve was examined unilaterally or bilaterally with surface electrodes (13 patients) or near nerve technique (45 patients). In case of bilaterally examined sural nerves, right side was chosen for analysis. Results were compared to laboratory controls. The pathophysiological state of sural nerve was classified as normal, axonal loss or demyelinating according to ESTEEM criteria (Tankisi et al., 2005). Results The mean conduction velocity (CV) was higher in CIDP (42.6 ± 5.6) and GBS (46.5 ± 8.1) than patients with PMP22 duplication (22.5 ± 5.3) (p 35 m/s). Sural NCS showed demyelination in all patients with PMP22 duplication and in 2 GBS whereas none of the CIDP patients had demyelination of the sural nerve. Normal sural nerve was seen in 10 GBS and in 5 CIDP patients whereas sural NCS showed axonal loss in 4 GBS and in 14 CIDP. Conclusion Sural NCS may help in differentiation of inflammatory and hereditary demyelination polyneuropathies. Demyelinating changes in sural nerve are characteristic for PMP22 duplication whereas axonal loss is mostly seen in CIDP and normal sural nerve NCS in GBS.

Diagnostic value of the near-nerve needle sensory nerve conduction in sensory inflammatory demyelinating polyneuropathy.

In this study we report the diagnostic value of the near-nerve needle sensory nerve conduction study (NNN-SNCS) in sensory inflammatory demyelinating polyneuropathy (IDP) in which the routine nerve conduction study was normal or non-diagnostic. The NNN-SNCS was performed to identify demyelination in the plantar nerves in 14 patients and in the median or ulnar nerve in 2 patients with sensory IDP. In 16 patients with sensory IDP, routine NCSs were either normal or non-diagnostic for demyelination. Demyelination was identified by NNN-SNCS by dispersion and/or slow nerve conduction velocity (NCV) below the demyelination marker. Immunotherapy was initiated in 11 patients, 10 of whom improved or remained stable. NNN-SNCS played an essential role in identifying demyelinaton in 16 patients with sensory IDP, leading to proper treatment. Muscle Nerve 57: 414-418, 2018.

Axonal loss in patients with inflammatory demyelinating polyneuropathy as determined by motor unit number estimation and MUNIX

ObjectiveThis study quantifies functioning axons and reinnervation by applying two methods multiple point stimulation (MPS) MUNE, and motor unit number index (MUNIX), in patients with acute- and chronic inflammatory demyelinating polyneuropathy (AIDP, CIDP). MethodsNineteen patients with inflammatory demyelinating polyneuropathy (eleven AIDP and eight CIDP) were prospectively included. MPS MUNE and MUNIX examinations on the thenar muscle group by stimulating the median nerve were applied on all patients. Motor unit size was calculated as single motor unit potential (sMUP) and motor unit size index (MUSIX). The results were compared with twenty healthy subjects. ResultsIn AIDP patients mean MPS MUNE (106) and MUNIX (80) were lower than control MPS MUNE (329) and MUNIX (215) (p<0.001). In CIDP patients both MPS MUNE (88) and MUNIX (67) were lower than controls (p<0.001). In CIDP patients sMUP (63) and MUSIX (90) were higher than control sMUP (35) and MUSIX (58) (p<0.05 and p<0.01). When AIDP and CIDP groups were combined the sensitivity for MPS MUNE and MUNIX were 89.5% and 68.4%, respectively. ConclusionsDecreased MPS MUNE and MUNIX suggest presence of axonal loss or loss of functioning axons in AIDP and CIDP. Increased motor unit size in CIDP patients indicates compensatory reinnervation. Moreover, both MPS MUNE and MUNIX can discriminate between disease versus non-disease. SignificanceEstimation of the number and the average size of motor units may have clinical value for the assessment of axonal loss or loss of functioning axons in patients with AIDP and CIDP.

Inflammatory demyelinating polyneuropathy with nephrotic syndrome: Report of a case and review of the literature

AbstractAn association between the acute or chronic form of inflammatory demyelinating polyneuropathy (IDP) and nephrotic syndrome has occasionally been reported. However, the clinical pictures in IDP of these cases have attracted little attention to date. In the present report, we describe a 50‐year‐old man with IDP who developed quadriplegia with respiratory impairment followed by a remitting and relapsing course for several months with complete recovery, in which nephrotic syndrome appeared at the nadir and subsided in parallel with the neurological improvement. We also searched for the English‐language literature from 1946 to 2012 April and found 32 cases of Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy with nephrotic syndrome. We analyzed the 33 cases including the present case, and found such features as: (i) male preponderance (84.8%); (ii) motor dominant impairments with favorable final outcomes; and (iii) proteinuria occurring simultaneously with neurological symptoms and ameliorating along with neurological improvement in the majority of the cases. Available data of nerve conduction studies consistently showed demyelinating neuropathy. These findings suggest that IDP with nephrotic syndrome might be a distinctive clinical entity possibly caused by immune reactions to antigen(s) shared by peripheral nerves and the glomerulus. As nephrotic syndrome is asymptomatic or transient in some cases, IDP with nephrotic syndrome might be more prevalent than we think.

Treatment Challenges for Inflammatory Demyelinating Polyneuropathy in the Setting of Acute Retroviral Syndrome: Case Report and Review of the Literature

This is a case of a 20-year-old male with acute retroviral syndrome and concurrent acute inflammatory demyelinating polyneuropathy (IDP) progressing to chronic IDP. Whereas the patient followed a relapsing and remitting course prior to the initiation of antiretroviral therapy (ART), he demonstrated gradual and sustained clinical improvement in the ten months of follow-up after ART was combined with chronic corticosteroids and intermittent plasmapheresis. This case presents and addresses multiple challenges for the treatment of IDP in the setting of acute HIV infection to include: timing of initiation and selection of appropriate ART, the potential risk for immune reconstitution inflammatory syndrome, ART initiation in the setting of severe gastroparesis with jejunostomy placement, and the effect of plasmapheresis on the levels of antiretroviral therapy.

Antibody-mediated rejection of the heart in the setting of autoimmune demyelinating polyneuropathy: a case report and review of the literature.

Background. Antibody-mediated rejection (AMR) is caused by the production of donor-specific antibodies (DSA) which lead to allograft injury in part via complement activation. The inflammatory demyelinating polyneuropathies (IDP) are inflammatory disorders of the nervous system, involving both cellular and humoral immune mechanisms directed against myelin. Case Report. A 58-year-old man five years after heart transplant presented with progressive dyspnea, imbalance, dysphagia, and weakness. Nerve conduction studies and electromyogram were consistent with IDP. Plasmapheresis and high-dose steroids resulted in improvement in neurologic symptoms. Within two weeks, he was readmitted with anasarca and acute renal failure, requiring intravenous furosemide and inotropic support. Echocardiogram and right heart catheterization revealed reduced cardiac function and elevated filling pressures. DSA was positive against HLA DR53, and endomyocardial biopsy revealed grade 1R chronic inflammation, with strong capillary endothelial immunostaining for C4d. Plasmapheresis and intravenous immunoglobulin (IVIG) were initiated. His anasarca and renal failure subsequently resolved, echocardiogram showed improved function off inotropes, and anti-DR53 MFI was reduced by 57%. Conclusions. This is an example of a single immune-mediated process causing concurrent IDP and AMR. The improvement in cardiac function and neurologic symptoms with plasmapheresis, IVIG, and high-dose steroids argues for a unifying antibody-mediated mechanism.

Clinical characteristics of Guillain-Barré syndrome in a tropical country: a Brazilian experience

To analyze the clinical variants, outcomes, and prognosis of Guillain-Barré syndrome (GBS) in a Brazilian population. Clinical and laboratory data of 149 cases of GBS diagnosed from 1994 to 2007 were analyzed. Acute inflammatory demyelinating polyneuropathy (AIDP) was the most frequent variant (81.8%) of GBS, followed by acute motor axonal neuropathy (AMAN) (14.7%) and acute motor and sensory axonal neuropathy (AMSAN) (3.3%). The incidence of GBS was 0.3/100,000 for the state of Rio Grande do Norte and cases occurred at a younger age. GBS was preceded by infections, with the axonal variant associated with episodes of diarrheas (P = 0.025). Proximal weakness was more frequent in AIDP, and distal weakness predominant in the axonal variant. Compared to 42.4% of cases with AIDP (P < 0.0001), 84.6% of cases with the axonal variant had nadir in <10 days. Individuals with the axonal variant took longer to recover deambulation (P < 0.0001). The mortality of GBS was 5.3%. A predominance of the AIDP variant was seen, and the incidence of the disease decreased with age. As expected, the distribution of weakness correlated with the clinical variants, and individuals with the axonal variant had a poorer prognosis.

Natural course of acute and chronic monophasic inflammatory demyelinating polyneuropathies (IDP). A retrospective analysis of 266 cases.

The present study analyses one of the largest IDP series published as yet: 266 cases, hospitalised between 1950 and 1983, conventionally treated and uniformly supervised. There was GBS in 84%, chronic IDP in 13%, polyneuritis cranialis in 1.5%, Miller Fisher and predominantly sensory neuropathy in 0.8% each. Numerous features including preceding events, course and outcome have been investigated. Latencies between onset and maximal deficit lacked (expected) bimodality. Sensory involvement was severe, mortality (18%) and maximal disability (20% requiring ventilation) high, autonomic dysfunction (71%) prominent. Statistical comparison of various features confirmed old age, rapid onset and need for ventilation as unfavorable predicting factors. However, preceding infection, bulbar paralysis and onset of paresis in proximal muscles evolved as unfavorable prognostic features as well.

Superficial radial sensory nerve potentials in immune-mediated and diabetic neuropathies

Objective The pattern of abnormal median-normal sural sensory nerve action potential (SNAP) is frequently found in acute/chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP), whereas sural/radial SNAP amplitude ratio is sensitive to detect dying-back degeneration. To investigate whether radial SNAP and its amplitude ratio to median or sural SNAP provide additional particular patterns of sensory nerve involvement. Methods Superficial radial, median, and sural SNAPs were recorded in 63 normal subjects and in 132 patients with AIDP/CIDP ( n=22), diabetic neuropathy ( n=83), or other axonal polyneuropathy ( n=27). Median/radial and sural/radial amplitude ratios were examined. Results In normal subjects, median/radial ratio was 0.96±0.05 (mean±SEM), and sural/radial ratio was 0.50±0.03. Compared with normal controls, the median/radial ratio was lower in patients with AIDP/CIDP (0.64±0.11; P<0.001) or diabetic neuropathy (0.75±0.04; P=0.08), but similar in those with other neuropathy (0.94±0.10). The sural/radial ratio was higher in the AIDP/CIDP group (0.71±0.08; P=0.10), and lower in the diabetic (0.36±0.03; P<0.001) and other axonal neuropathy groups (0.40±0.07; P=0.08). Conclusions AIDP/CIDP is associated with a reduced median/radial ratio and increased sural/radial ratio, probably reflecting demyelination predominant in the distal nerve terminals. Diabetic neuropathy is characterized by decreases in both median/radial and sural/radial ratios, presumably due to coexistence of carpal tunnel pathology and dying-back degeneration. Significance Comparison of multiple SNAP amplitudes provides information about characteristic distribution patterns of sensory nerve involvement in peripheral neuropathies.

Chronic Inflammatory Demyelinating Polyneuropathy and Membranous Glomerulonephropathy: Report of Two Cases

Chronic inflammatory demyelinating polyneuropathy (CIDP) may develop as an isolated, idiopathic disorder or may occur with a temporal relationship to other systemic disorders. We report two cases of chronic inflammatory demyelinating polyneuropathy and membranous glomerulonephropathy (MGN) occurring in the same patients. In each case, the two disorders manifested in close proximity to each other. These two cases supplement previously reported cases of MGN as a coincident and potentially causally related comorbidity to CIDP. We review previous reports of MGN associated with the full spectrum of inflammatory demyelinating polyneuropathies (IDP).

Can antiglycolipid antibodies present in HIV-infected individuals induce immune demyelination?

Of the eight clinically defined neuropathies associated with HIV infection, there is compelling evidence that acute and chronic inflammatory demyelinating polyneuropathy (IDPN) have an autoimmune pathogenesis. Many non-HIV infected individuals who suffer from sensory-motor nerve dysfunction have autoimmune indicators. The immunopathogenesis of demyelination must involve neuritogenic components in myelin. The various antigens suspected to play a role in HIV-seronegative IDPN include (i) P2 protein; (ii) sulfatide (GalS); (iii) various gangliosides (especially GM1); (iv) galactocerebroside (GalC); and (v) glycoproteins or glycolipids with the carbohydrate epitope glucuronyl-3-sulfate. These glycoproteins or glycolipids may be individually targeted, or an immune attack may be raised against a combination of any of these epitopes. The glycolipids, however, especially GalS, have recently evoked much interest as mediators of immune events underlying both non-HIV and HIV-associated demyelinating neuropathies. The present review outlines the recent research findings of antiglycolipid antibodies present in HIV-infected patients with and without peripheral nerve dysfunction, in an attempt to arrive at some consensus as to whether these antibodies may play a role in the immunopathogenesis of HIV-associated inflammatory demyelinating polyneuropathy.

Can antiglycolipid antibodies present in HIV‐infected individuals induce immune demyelination?

Of the eight clinically defined neuropathies associated with HIV infection, there is compelling evidence that acute and chronic inflammatory demyelinating polyneuropathy (IDPN) have an autoimmune pathogenesis. Many non‐HIV infected individuals who suffer from sensorymotor nerve dysfunction have autoimmune indicators. The immunopathogenesis of demyelination must involve neuritogenic components in myelin. The various antigens suspected to play a role in HIV‐seronegative IDPN include (i) P2 protein; (ii) sulfatide (GalS); (iii) various gangliosides (especially GM1); (iv) galactocerebroside (GalC); and (v) glycoproteins or glycolipids with the carbohydrate epitope glucuronyl‐3‐sulfate. These glycoproteins or glycolipids may be individually targeted, or an immune attack may be raised against a combination of any of these epitopes. The glycolipids, however, especially GalS, have recently evoked much interest as mediators of immune events underlying both non‐HIV and HIV‐associated demyelinating neuropathies. The present review outlines the recent research findings of antiglycolipid antibodies present in HIV‐infected patients with and without peripheral nerve dysfunction, in an attempt to arrive at some consensus as to whether these antibodies may play a role in the immunopathogenesis of HIV‐associated inflammatory demyelinating polyneuropathy.

HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment.

Peripheral neuropathy is the most frequent neurological complication associated with human immunodeficiency virus type 1 (HIV) infection and advanced acquired immunodeficiency syndrome (AIDS). There are at least 6 patterns of HIV-associated peripheral neuropathy, although these diagnoses are often overlooked or misdiagnosed. Distal symmetrical polyneuropathy (DSP) is the most common form of peripheral neuropathy in HIV infection. DSP occurs mainly in patients with advanced immunosuppression and may also be secondary to the neurotoxicity of several antiretroviral agents. Treatment of painful DSP is primarily symptomatic, while pathogenesis-based therapies are under investigation. Reduction or discontinuation of neurotoxic agents should be considered if possible. Inflammatory demyelinating polyneuropathy (IDP) can present in an acute or chronic form. The acute form may occur at the time of primary HIV infection or seroconversion. Cerebrospinal fluid lymphocytic pleocytosis (10 to 50 cells/mm3) is helpful in the diagnosis of HIV-associated IDP. Treatment consists of immunomodulatory therapy. Progressive polyradiculopathy (PP) most commonly occurs in advanced immunosuppression and usually is caused by cytomegalovirus (CMV) infection. Rapidly progressive flaccid paraparesis, radiating pain and paresthesias, areflexia and sphincter dysfunction are the cardinal clinical features. Rapid diagnosis and treatment with anti-CMV therapy are necessary to prevent irreversible neurological deficits resulting from nerve root necrosis. Mononeuropathy multiplex (MM) that occurs in early HIV infection is characterised by self-limited sensory and motor deficits in the distribution of individual peripheral nerves. In advanced HIV infection, multiple nerves in two or more extremities or cranial nerves are affected. Treatment includes immunomodulation or anti-CMV therapy. Autonomic neuropathy may be caused by central or peripheral nervous system abnormalities. Treatment is supportive with correction of metabolic or toxic causes. Diffuse infiltrative lymphocytosis syndrome (DILS) presents as a Sjögren's-like disorder with CD8 T cell infiltration of multiple organs. Antiretroviral therapy and steroids may be effective treatments.

Peripheral neuropathy in HIV disease.

Neurologic disorders are among the most common and devastating complications of HIV infection and AIDS.1 As patients with HIV infection survive longer in the era of HAART, it is likely that the prevalence of these disorders will increase. Peripheral nerve disorders are the most common neurologic complication of HIV disease.2 HIV-related peripheral nerve disorders include distal symmetric polyneuropathy (DSP), acute or chronic inflammatory demyelinating polyneuropathy (IDP), mononeuritis multiplex (MM), progressive polyradiculopathy (PP), and autonomic neuropathy (AN). Data from ACTG protocol 175 indicate that neuropathy is frequently misdiagnosed, even by experienced clinicians.3 In order to provide effective treatment, it is essential to distinguish among the various forms of neuropathy and to correctly attribute them to primary HIV infection or to other causes, such as the neurotoxic effects of antiviral agents. Although peripheral neuropathy is generally not a life-threatening disease, the debilitating pain can severely impair the quality of life of affected individuals. Of particular importance is distal sensory polyneuropathy (DSP), the most common form of peripheral neuropathy and the only one associated with the use of antiretroviral therapy. DSP affects over one third of patients with AIDS. It is rarely seen in children and is most common in the late stages of HIV disease. The clinical symptoms of DSP are numbness, burning, and tingling sensations in the feet, usually in a symmetric pattern; paresthesias or aching distally in the lower extremities; and hyperesthesia (e.g., contact sensitivity, such as with bedsheets or socks). Individuals with DSP may alter their gait in order to avoid painful pressure on their feet, which can result from even light contact. In late stages of DSP, the upper extremities may also be affected, although to a milder degree. Neurologic examination reveals depressed or absent ankle reflexes relative to the knees. While this is a …

Magnetic nerve root stimulation in two types of brachial plexus injury: Segmental demyelination and axonal degeneration

Magnetic cervical nerve root stimulation was performed in 9 patients with plexopathies secondary to suspension (SP) and in 12 cases with neurogenic thoracic outlet syndrome (NTOS). The findings were compared with those of the previously reported case groups: n-hexane polyneuropathy (HPNP), inflammatory demyelinating polyneuropathy (IDP), and motor neuron disease (MND). Muscle responses elicited by magnetic stimulation had very high rates of amplitude and area loss in the neck-axilla segments of the 6 SP patients. This, along with the other electrophysiological findings, suggested the presence of segmentally demyelinating plexus lesions. In NTOS patients, magnetic stimulation findings were not significantly different from those of the controls. Neck-axilla segment amplitude and are reduction rates in SP and IDP patients were significantly higher than those found in NTOS, HPNP, and MND groups, implying that magnetic nerve root stimulation may have a role in the demonstration of segmentally demyelinating lesions involving proximal nerve segments.

Intravenous Gamma-Globulin Therapy

Initially used as replacement therapy in patients with hypogammaglob-ulinemia, intravenous gamma-globulin (IVIg) preparations are increasingly being used as treatment for various autoimmune disorders. Although expensive, IVIg has become first-line or adjunctive therapy in the treatment of disorders as diverse as autoimmune or post-transfusion thrombocytopenia, autoimmune hemolytic anemia, Kawasaki's disease, inflammatory myositis, myasthenia gravis, pediatric acquired immune deficiency syndrome, bone marrow transplantation, and inflammatory de-myelinating polyneuropathy. IVIg remains the first line of therapy in patients with humoral immunodeficiency syndromes. Clinical studies support the selective use of this therapy in the above disorders; it has also been tried as therapy in many other diseases, with varied results. IVIg therapy has received Food and Drug Administration approval for use as maintenance treatment of patients with primary humoral immunodeficiencies and as therapy for acute or chronic autoimmune thrombocytopenic purpura.

Guillain‐Barré syndrome associated with human immunodeficiency virus infection in Zimbabwe

We studied the clinical features and human immunodeficiency virus (HIV) serology of 32 consecutive adults with inflammatory demyelinating polyneuropathy (IDP) admitted to the teaching hospitals in Harare, Zimbabwe. Twenty-nine of the IDP patients had Guillain-Barré syndrome (GBS), and the other three had chronic IDP. Sixteen of 29 (55%) GBS patients were HIV-seropositive, a higher frequency of HIV infection than in blood donors drawn from the population served by these hospitals. All three chronic IDP patients were HIV-seronegative. In all HIV-seropositive patients, GBS was the initial illness that brought the patient to medical attention and led to the diagnosis of HIV infection. Compared with seronegative patients, the HIV-seropositive GBS patients were more likely to have generalized lymphadenopathy, CSF pleocytosis, coexistent CNS disturbance, and prior sexually transmitted disease. GBS in this region of Africa is frequently associated with HIV infection.

The spectrum of changes on 20 nerve biopsies in patients with HIV infection

Nerve and muscle biopsies were performed on 20 patients with HIV infection and peripheral neuropathy. Nine patients had distal symmetrical peripheral neuropathy (DSPN) (six ARC and three AIDS), six had inflammatory demyelinating polyneuropathy (IDP) (three ARC, one AIDS, and two otherwise asymptomatic patients), one had mononeuropathy multiplex (MM) (AIDS), 1 had mononeuropathy (ARC), one had meningoradiculitis (AIDS), and two had areflexia-associated lymphocytic meningitides (ARC), DSPN exhibited axonal degeneration in four of nine cases and was associated with segmental demyelination in five of nine cases. IDP exhibited segmental demyelination associated with axonal degeneration in four of six cases. Demyelination was more frequent in asymptomatic patients (2 of 2 cases) and in ARC (7 of 12 cases), whereas axonal degeneration was predominant in AIDS (6 of 6 cases). Mononuclear cell infiltration was seen in 1 of 2 asymptomatic patients and in 11 of 12 ARC patients but was exceptionally found in AIDS (1 of 6 cases). Involvement of the walls of small vessels, mostly venules ("subacute microvasculitis"), was found in 1 of 2 asymptomatic patients, in 8 of 12 ARC patients, and never in AIDS. The polyclonal mononuclear cell population was composed mainly of Leu 2 (T8) positive cells in seven cases of ARC. No virions were seen in electron microscopy. HIV was isolated in two cases from the CSF or the nerve biopsy.