Toshiki Fujioka

Astrocytes as antigen-presenting cells: expression of IL-12/IL-23

Interleukin‐12 (IL‐12, p70) a heterodimeric cytokine of p40 and p35 subunits, important for Th1‐type immune responses, has been attributed a prominent role in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the related heterodimeric cytokine, IL‐23, composed of the same p40 subunit as IL‐12 and a unique p19 subunit, was shown to be involved in Th1 responses and EAE. We investigated whether astrocytes and microglia, CNS cells with antigen‐presenting cell (APC) function can present antigen to myelin basic protein (MBP)‐reactive T cells, and whether this presentation is blocked with antibodies against IL‐12/IL‐23p40. Interferon (IFN)‐γ‐treated APC induced proliferation of MBP‐reactive T cells. Anti‐IL‐12/IL‐23p40 antibodies blocked this proliferation. These results support and extend our previous observation that astrocytes and microglia produce IL‐12/IL‐23p40. Moreover, we show that stimulated astrocytes and microglia produce biologically active IL‐12p70. Because IL‐12 and IL‐23 share p40, we wanted to determine whether astrocytes also express IL‐12p35 and IL‐23p19, as microglia were already shown to express them. Astrocytes expressed IL‐12p35 mRNA constitutively, and IL‐23 p19 after stimulation. Thus, astrocytes, under inflammatory conditions, express all subunits of IL‐12/IL‐23. Their ability to present antigen to encephalitogenic T cells can be blocked by neutralizing anti‐IL‐12/IL‐23p40 antibodies.

Ischemic and hemorrhagic brain stem lesions mimicking diabetic ophthalmoplegia

Two patients with diabetes mellitus, one of them with an isolated third cranial nerve palsy and the other with an isolated sixth cranial nerve palsy, are presented. MRI investigations including diffusion-weighted MRI revealed a small ischemic brain stem lesion in the former and a small hemorrhagic brain stem lesion in the latter. In the former case wallerian degeneration of the nerve fascicle within the mesencephalon was also detected. These cases indicate that vascular accidents of the brain stem may masquerade as fascicular or infranuclear disturbance of the oculomotor or abducens nerve; therefore, it is important to include brain stem lesions into the differential diagnosis of isolated ophthalmoplegia. Thorough investigation by MRI including diffusion-weighted MRI is helpful for correct diagnosis.

Reversible Cerebellar Lesions Induced by Metronidazole Therapy for Helicobacter Pylori

Metronidazole is widely used for chronic or refractory infection and has recently also been used for the treatment of Helicobacter pylori. The authors report the case of a Japanese patient presenting with reversible cerebellar lesions induced by prolonged administration of metronidazole for treatment of H pylori with magnetic resonance imaging findings. Although rare, prolonged and high‐dose administration of metronidazole may induce cerebellar lesions. Increased awareness of this phenomenon is important, as these lesions are reversible with discontinuation of this drug.

Anti-TNF therapy using etanercept suppresses degenerative and inflammatory changes in skeletal muscle of older SJL/J mice.

Limb-girdle muscular dystrophy 2B and Miyoshi myopathy are characterized by muscle fiber necrosis caused by a defect in dysferlin and inflammatory changes. SJL/J mice are deficient in dysferlin and display severe inflammatory changes, most notably the presence of cytokines, which may be related to destruction of the sarcolemma. We tested the hypothesis that tumor necrosis factor (TNF) contributes to myofibril necrosis. Administration of etanercept, an agent that blocks TNF, resulted in dose-dependent reductions in inflammatory change, necrosis, and fatty/fibrous change. These findings indicate that TNF does indeed play a role in the damage to muscle in SJL/J mice and that etanercept has the potential to reduce such damage.

Beneficial effect of pramipexole for motor function and depression in Parkinson's disease.

We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson’s disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson’s Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.

A case of Vernet syndrome with varicella zoster virus infection.

A 40-year-old man was admitted to our department, because of sudden onset of dysphagia, hoarseness, left neck pain and headache. There were no skin lesions. On neurological examination, there were paralysis of the left soft palate and constrictor muscles of the pharynx, weakness of the left sternocleidomastoid and left upper trapezius. In cerebrospinal fluid (CSF) examination, cell count and protein concentration were elevated. Antibody titer to varicella zoster virus (VZV) was elevated in both the serum and CSF. And VZV-DNA was detected by PCR from CSF. Gd enhanced MRI showed the nodular lesion at the left jugular foramen. The diagnosis of Vernets syndrome (VS) associated with VZV infection was made. The patients symptoms were immediately improved with 30 mg of prednisone and 3 g of varaciclovir daily for 14 days. Only a few cases of VS due to VZV have been reported previously. Our case is the first case that detected VZV-DNA in CSF by PCR.

A case of Guillain-Barré syndrome associated with cerebellar ataxia and positive serum anti-GD1b IgG antibody

Sirs: It is well known that the antibody against ganglioside is detectable in the Guillain-Barré syndrome (GBS) [2, 5, 9]. AntiGD1b IgG antibody has been found in a case of ataxia with disturbance of deep sensation [7]. We encountered a case of GBS associated with cerebellar type ataxia and positive serum anti-GD1b IgG antibody. A 21-year-old woman presented on 9 May 1999, suffering from diarrhoea. On 20 May, she felt weakness in the lower extremities and later developed paraesthesia in the distal part of both extremities and diplopia. On 26 May, she had difficulty in walking. On 3 June, she was admitted to our hospital. On admission, neurological examination revealed normal consciousness. In the cranial nerves, a left abducens paralysis was found. The muscle strength was 3/5 in all extremities. Grip strength was 2 kg on the right side and 3 kg on the left side. All deep tendon reflexes were diminished and pathological reflexes were not observed. Objective sensations were all normal. Rectal sphincter and bladder dysfunction and cerebellar signs were not observed. Laboratory studies disclosed that Campylobacter jejuni was not detected in her faeces. Serum antiGD1b IgG antibody titre was 1:200 (normal < 100). Anti-GM1, GM2, GD1a,GD1b, GT1b and GQ1b antibody titres were all within normal ranges. Cerebero-spinal fluid examination revealed that the cell count was 2/μl, total protein was 217 mg/dl, and sugar was 54 mg/dl (blood sugar 88 mg/dl). Electrophysiological examination revealed that the motor nerve conduction velocity was 37.1 m/s (normal > 43.0) in the right peroneal nerve and 36.6 m/s (normal > 41.0) in the right tibial nerve. Sensory nerve conduction velocity was not detected in the right peroneal nerve and was 39.9 m/s (normal > 46.0) in the right tibial nerve. After admission, she was immediately treated with immuno-absorption therapy (tryptophan calumn; TR-250). After beginning the 1st immuno-absorption therapy, cerebellar speech appeared. Subsequently, disturbance of finger-nose and heel-knee tests, intention tremor, dysmetria and dysdiadochokinesis were observed; however, Romberg’s sign and disturbance of deep sensation were not detected. After 4 courses of immuno-absorption therapy, muscle weakness, paraesthesia and disturbance of eye movement gradually improved, but did not completely disappear. The delayed cerebellar signs also improved by the end of June, and she discharged herself. At this point, serum anti-GD1b IgG antibody titre was still elevated at 1:200. However, following discharge, exacerbation occurred after a few days, including muscle weakness mostly in the upper extremities and paraesthesia. After re-admission another 4 courses of immuno-absorption therapy were administered. At the end of August, her symptoms all subsided, with normal serum anti-GD1b IgG antibody titre (< 1:100). Head MRI was performed twice during her admission, but no abnormal signs were detected in the cerebrum, cerebellum or brain stem. The clinical course is shown in Figure. In the present case, muscle weakness, paraesthesia and diminished deep tendon reflexes occurred, followed by diarrhoea, and LETTER TO THE EDITORS

Myasthenia gravis and invasive thymoma. A 20-year experience.

Over the last 20 years, 15 patients with myasthenia gravis and invasive thymoma have been treated in our department. Eight of these patients underwent either nontotal excision or were not operated on due to massive invasion, while 7 underwent total excision. These 15 cases represent 6.2% of the 242 myasthenic patients treated during this period. Six of the 8 nontotal excision cases died, and 2 of the 7 total excision cases succumbed. The prognosis of total excision cases was better than that of nontotal excision cases. The overall 5-year survival rate was 73%, and the 10-year survival rate 20%. Total excision of the thymoma, if possible, and high doses of corticosteroids and combination chemotherapy for the remaining tumor seem to be the treatments of choice.

Guillain-Barré syndrome with optic neuritis and cytomegalovirus infection.

Dear Editor, Although the cranial nerves are often involved in Guillain-Barré syndrome (GBS), the optic nerves are usually spared presumably because they are part of the central nervous system (CNS). Here, we report a case of GBS with concurrent optic neuritis (ON) with antecedent cytomegalovirus (CMV) infection. This combination suggests that some epitope shared with both the CNS and peripheral nervous system (PNS) was targeted by an autoimmune process triggered by CMV infection. A previously healthy 68-year-old man noticed visual loss in the right eye when he woke up and had cough and low-grade fever 4 days prior. Examination the next day revealed no light perception on either eye with normal optic discs, fundi and ocular movements. The peripheral facial nerve and the right hypoglossal nerve palsies in the right side were present. Three days after disease onset, he developed bilateral ophthalmoplegia and bulbar palsy. On day 4, he developed muscle weakness in the upper extremities and respiratory failure. On day 5, quadriplegia, loss of deep tendon reflexes, and sensory disturbance in all modalities were noted. The nerve conduction studies were consistent with primary demyelination. The visual evoked potential could not be obtained. The cerebrospinal fluid protein was elevated to 209 mg/dL with normal cell count (4/mL, M : P 1⁄4 1 : 3). Myelin basic protein and oligoclonal immunoglobulin G (IgG) bands were negative. MRI of the brain and optic nerves was normal. The serum titers of IgG anti-GQ1b, anti-GT1a antibodies increased on days 4, 11, and 41, normalized on day 74. The antibody titers against CMV were significantly high during the clinical course (Table 1). He was diagnosed as having atypical GBS. High-dose intravenous immunoglobulin (0.4 mg/kg/ day for 5 days) alleviated his symptoms except for ON. A course of intravenous methylprednisolon pulse therapy (1 g/day for 3 days) was employed on day 31 and resulted in gradual recovery of visual acuity. After 6 months, he could walk more than one kilometer without support and could count fingers with either eye. The unique point of this case is that descending paralysis with multiple cranial nerve involvement started from the optic nerves. On admission, the diagnosis of GBS was unclear because his neurological signs were restricted to the cranial nerves including bilateral optic nerves recognized as part of the CNS. Within a few days, however, bulbar palsy with respiratory failure and motor-sensory peripheral neuropathy became evident. GBS, an acute generalized inflammatory demyelinating peripheral nerve disorder, rarely complicates CNS involvements including, if any, lesions in the cerebral white matter, the brain stem, the spinal cord, or the optic nerves. In most reported GBS cases with ON, the temporal profile of GBS is different from that of ON (Nikoskelainen and Riekkinen, 1972; Behan et al., 1976; Nadkarni and Lisak, 1993). This biphasic clinical profile suggests that an autoantigen, not pathogenic for the first lesion, was liberated from the nervous system during the first attack and subsequently sensitized the host to cause the second insult (Behan et al., 1976). In the present case, however, GBS and ON developed synchronously. This indicates that an epitope shared in both the CNS and PNS was targeted. The mechanism is still unknown, but the involvement of CMV infection, serologically confirmed in the present case, is speculated. Some cases with concurrent GBS and ON have the evidence of direct infection of mumps virus (Bajaj et al., 2001) or Mycoplasma pneumoniae (Henderson et al., 1998). CMV, a potent neurotropic virus, is a common antecedent infectious agent of GBS as well (Visser et al., 1996; Hadden et al., 2001). Whether there is a linkage of GBS with ON and anti-ganglioside antibody (GQ1b or GT1a) and CMV infection remains unclear, however, the fact that Address correspondence to: Dr. Toshiki Fujioka, Department of Neurology, Toho University Medical Centre Omori Hospital, 6-11-1 Omori-nishi Ota-ku, Tokyo 143–8541, Japan. Tel: þ81-3-3762-4151; Fax: þ81-3-3768-2566; E-mail: fujioka@med.toho-u.ac.jp Journal of the Peripherl Nervous System 10:340–341 (2005)

T-588 Protects Motor Neuron Death Following Axotomy

R(—)-1-(benzo [b] thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy] ethanol hydrochloride) (T-588) enhances acetylcholine release. This compound slows the motor deterioration of wobbler mouse motor neuron disease and enhances neurite outgrowth and choline acetyltransferase activity in cultured rat spinal motor neurons. We examined the ability of T-588 on axotomized spinal motor neuron death in the rat spinal cord. After the postnatal unilateral section of sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment. In comparison with vehicle, intraperitoneal injection of T-588 for 14 consecutive days rescued spinal motor neuron death. Our results showing in vivo neurotrophic activity of T-588 for motor neurons support the applicability of T-588 for the treatment of motor neuron diseases, such as amyotrophic lateral sclerosis and motor neuropathies.