Akiyuki Hiraga

Does Campylobacter jejuni infection elicit “demyelinating” Guillain–Barré syndrome?

Background: Campylobacter jejuni enteritis is the most common antecedent infection in Guillain–Barré syndrome (GBS). C. jejuni-related GBS is usually acute motor axonal neuropathy (AMAN), but previous reports described many cases of the demyelinating subtype of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) after C. jejuni infection. Objective: To investigate whether C. jejuni infection elicits AIDP. Methods: In 159 consecutive patients with GBS, antibodies against C. jejuni were measured using ELISA. Antecedent C. jejuni infection was determined by the strict criteria of positive C. jejuni serology and a history of a diarrheal illness within the previous 3 weeks. Electrodiagnostic studies were performed weekly for the first 4 weeks, and sequential findings were analyzed. Results: There was evidence of recent C. jejuni infection in 22 (14%) patients. By electrodiagnostic criteria, these patients were classified with AMAN (n = 16; 73%) or AIDP (n = 5; 23%) or as unclassified (n = 1) in the first studies. The five C. jejuni-positive patients with the AIDP pattern showed prolonged motor distal latencies in two or more nerves and had their rapid normalization within 2 weeks, eventually all showing the AMAN pattern. In contrast, patients with cytomegalovirus- or Epstein–Barr virus-related AIDP (n = 13) showed progressive increases in distal latencies in the 8 weeks after onset. Conclusion: Patients with C. jejuni-related Guillain–Barré syndrome can show transient slowing of nerve conduction, mimicking demyelination, but C. jejuni infection does not appear to elicit acute inflammatory demyelinating polyneuropathy.

Recovery patterns and long term prognosis for axonal Guillain–Barré syndrome

Background: Little is known about the long term prognosis for patients the severe acute motor axonal neuropathy (AMAN) form of Guillain–Barré syndrome (GBS), unlike those with acute inflammatory demyelinating neuropathy (AIDP). Objective: To clarify the long term prognosis for patients with AMAN. Methods: Clinical recovery and outcome in 97 consecutive GBS patients were reviewed. Results: Electrodiagnostic criteria showed that 44 patients (45%) had AMAN, 33 (34%) had AIDP, and 20 (21%) were unclassified. Most of the severely affected patients had received plasmapheresis or immunoglobulin therapy. Slow recovery (inability to walk independently at six months after onset) was found in six of the AMAN patients (14%) and in two of the AIDP patients (6%). Of the six AMAN patients, four could walk independently one year after the onset, and the other two could walk independently at 28 and 57 months after onset. Of the two AIDP patients, one could walk at nine months after the onset while the other died of pneumonia seven months after onset. Conclusions: AMAN electrodiagnosis is not always a marker of poor recovery. Almost all the severe AMAN patients who had slow recoveries over the first six months could eventually walk independently, although some required several years.

Rho‐kinase inhibition enhances axonal regeneration after peripheral nerve injury

Abstract  In injured adult neurons, the process of axonal regrowth and reestablishment of the neuronal function have to be activated. We assessed in this study whether RhoA, a key regulator of neurite elongation, is activated after injury to the peripheral nervous system. RhoA is activated in motoneurons but not in Schwann cells after mouse sciatic nerve injury. To examine whether the activation of RhoA and its effector, Rho‐kinase, retards axon regeneration of injured motoneurons, we employed a Rho‐kinase inhibitor, fasudil. Amplitudes of distally evoked compound muscle action potentials are increased significantly faster after axonal injury in mice treated with fasudil compared with controls. Histological analysis shows that fasudil treatment increases the number of regenerating axons with large diameter, suggesting that axon maturation is facilitated by Rho‐kinase inhibition. In addition, fasudil does not suppress the myelination of regenerating axons. These findings suggest that RhoA/Rho‐kinase may be a practical molecular target to enhance axonal regeneration in human peripheral neuropathies.

Changes in excitability properties associated with axonal regeneration in human neuropathy and mouse Wallerian degeneration

OBJECTIVE The aim of this study was to investigate changes in excitability properties associated with axonal regeneration in human neuropathy and a mouse Wallerian degeneration model. METHODS Threshold tracking was used to measure axonal excitability indices such as strength-duration time constant (SDTC), threshold electrotonus, supernormality in median motor axons at the wrist of 13 patients with vasculitic neuropathy in their recovery phase, and in tibial motor axons at the ankle of mice with sciatic nerve crush. In the mouse model, excitability testing was performed 4, 8, 12, and 20weeks after the nerve crush. RESULTS In patients, there were longer SDTC, greater threshold changes at 0.2ms in latent addition, and greater threshold changes in depolarizing and hyperpolarizing threshold electrotonus, compared with controls. The pattern of changes in excitability indices was similar to those in experimental nerve crush, in which the indices remained abnormal for 20weeks after the crush. These changes suggest an increase in nodal persistent sodium currents, whereas multiple factors may also contribute to changes in excitability properties, such as axonal hyperpolarization, increased internodal resistance, and altered potassium currents. CONCLUSIONS Excitability properties in regenerating axons are characterized by increased nodal persistent currents with variable combination of changes in passive properties, membrane potential, and potassium currents. SIGNIFICANCE Increased persistent sodium currents are potential reasons for positive symptoms in patients with axonal neuropathy. Sodium channel blockers could be considered a treatment option.

The effects of mexiletine on excitability properties of human median motor axons

OBJECTIVE To investigate the effects of mexiletine, an analog of lidocaine, on excitability of human axons in vivo. METHODS Threshold tracking was used to measure multiple excitability indices (strength-duration time constant, rheobase, refractoriness, supernormality, and threshold electrotonus) in median motor axons of 20 patients with neuropathic pain or muscle cramping, before and 3 months after treatment with oral 300 mg mexiletine per day. RESULTS After treatment, there was a reduction in pain/muscle cramps, associated with decreased strength-duration time constants (P=0.01), increased rheobasic currents (P=0.06), and lower refractoriness (P=0.02), all of which were consistent with reduced nodal Na+ currents. Supernormality and threshold electrotonus did not change significantly. The changes in strength-duration properties suggest a decrease in persistent Na+ conductance. The lowered refractoriness after treatment might result from reduced transient Na+ currents, but the lack of change in supernormality and threshold electrotonus was not consistent with this hypothesis. CONCLUSIONS Oral mexiletine in a dosage of 300 mg daily suppresses persistent Na+ currents in human motor axons. SIGNIFICANCE Measurements of the excitability indices can be used for non-invasive assessment and monitoring of the effects of mexiletine in patients with neuropathic pain or muscle cramps.

Primary Sjogren's syndrome presenting with generalized autonomic failure

A 64 year‐old woman developed Raynauds phenomenon and dry eyes/mouth. Laboratory examination revealed positive Schirmers test, rheumatoid factor and anti‐nuclear antibody, and lymphocytic sialoadenitis on salivary gland biopsy. These features strongly suggested the diagnosis of primary Sjogrens syndrome. Three years later, she gradually developed generalized autonomic failure without apparent sensory neuropathy on nerve conduction study. She had systolic pressure fall of 51 mmHg on head‐up tilt test, cardiovascular supersensitivity to diluted norepinephrine infusion, cardiac denervation in [123I]‐MIBG scintigraphy, impaired R‐R variability, decreased sweating and prolonged colonic transit time. Autoimmune autonomic ganglionopathy was mostly responsible for her autonomic failure.

Axonal potassium conductance and glycemic control in human diabetic nerves

OBJECTIVE To investigate the effects of hyperglycemia on axonal excitability and potassium conductance in human diabetic nerves. METHODS Threshold tracking was used to measure excitability indices, which depend on potassium channels (supernormality, late subnormality, threshold electrotonus, and a current/threshold relationship) in median motor axons of 96 diabetic patients. The effects of hyperglycemia on these indices were analyzed. RESULTS Among diabetic patients, higher serum hemoglobin A1c (HbA1c) levels were significantly associated with greater supernormality (P = 0.04) and smaller late subnormality (P = 0.02), suggestive of reduced nodal/paranodal potassium currents under hyperglycemia. Threshold electrotonus and current/threshold relationships did not correlate with HbA1c levels, but partly related with nerve conduction slowing. CONCLUSIONS Hyperglycemia could reduce nodal potassium conductances, possibly due to reduced membranous potassium gradient or suppression of potassium channels. In contrast, internodal potassium conductances may be determined by both metabolic factors and structural changes such as exposure of internodal channels by demyelination. SIGNIFICANCE Measurements of the excitability indices could provide new insights into nodal and internodal axonal membrane properties in human diabetic neuropathy, whereas multiple factors can affect especially internodal properties.

Physicochemical property changes of amino acid residues that accompany missense mutations in SCN1A affect epilepsy phenotype severity

Background: Several different missense mutations in the voltage-gated sodium channel subunit gene SCN1A have been identified in epileptic patients with benign phenotype and patients with severe phenotype. However, the reason why similar missense mutations in SCN1A result in different phenotypes has not yet been fully clarified. Objective: To clarify the phenotype–genotype relationship in SCN1A, a meta-analysis was performed to quantitatively determine the effect of amino acid substitutions in SCN1A on epilepsy severity phenotype using physicochemical property indices of the amino acid, and to discuss in the context of the molecular evolution of the proteins. Methods: PubMed was searched for articles and information was extracted on localisation and types of SCN1A missense mutations in patients with benign and severe epileptic syndromes; detailed information was also extracted. Results: Meta-analysis quantitatively revealed that the physicochemical properties of several amino acids significantly affected epilepsy phenotype severity. It showed that missense mutations that decreased protein hydrophobicity were significantly associated with severe epilepsy phenotypes. It also showed that the phenotype severity of SCN1A missense mutations in the transmembrane domains of SCN1A (128/155; 82.6%) could be predicted with high sensitivity and positive predictive values using the physicochemical property changes, indicating the possibility of phenotype prediction for entirely new missense mutations using analytical methods. Conclusions: The results show that changes in the physicochemical properties of amino acids affected both the phenotype and clinical symptoms of patients with SCN1A missense mutations. This meta-analysis study provides new insights into SCN1A gene functions and a new strategy for genetic diagnosis, genetic counselling and epilepsy treatment.

Voltage-gated potassium channel antibody-associated encephalitis with basal ganglia lesions

Antibodies reactive with neuronal voltage-gated potassium channels (VGKCs) have been reported in patients with limbic encephalitis, which affects the medial temporal lobes and is characterized by subacute onset of temporal lobe seizures, memory impairment, and personality changes.1–5 MRI of those patients showed only abnormal signal intensity located in the medial temporal lobes.1–5 We describe a patient with encephalitis associated with anti-VGKC antibody who had MRI abnormalities localized in the basal ganglia as well as in the medial temporal lobes that improved dramatically on corticosteroid treatment. A previously healthy, 23-year-old woman presented with a generalized seizure and was admitted to a nearby hospital, 2 months after onset of repeated short-term fevers with cervical lymphadenopathy. She showed disorientation and memory loss. Brain CT was negative. A CSF examination showed pleocytosis (12 lymphocytes/mm3) and a normal protein level. Viral encephalitis was diagnosed, and she was prescribed IV acyclovir. She continued to show severe memory loss and childishness. Brain MRI done 17 days after admission showed symmetric abnormal signal intensities localized in the bilateral …

Over 10 years of isolated autonomic failure preceding dementia and Parkinsonism in 2 patients with Lewy body disease

nied by pouting have also been observed, and together, these movements have been termed oral automatisms.3,9 The spectrum of involuntary, patterned movement encountered in LIS also includes movements that appear emotionally charged, including movements accompanied by vocalization. Grunting, groaning, sighing, yawning, moaning, crying, and the pain reaction are all described.3,9 The presence of these movements would suggest spontaneous activity within the motor component of the emotional motor system thought to reside between the midbrain periaqueductal gray matter and interneurons in the caudal medulla.10 We believe that the locked-in state and development of symptomatic palatal tremor is particularly well illustrated by this case.