A 38-year-old Japanese man was admitted to our hospital because of muscle weakness in his lower extremities. His and his family’s histories were unremarkable. Fifteen days before admission, he had a mild fever with fatigue. Simultaneously, itchy skin rashes emerge on his foot and face, particularly around his mouth. The patient was tentatively diagnosed as having hand, foot, and mouth disease. Prior to admission, his fever, fatigue, and skin rash began to resolve, but the lower limb weakness progressively worsened within a few days. On admission, his general condition was unremarkable. A neurological examination showed that he was alert and oriented. His higher cerebral functions and cranial nerves were intact. The patient showed spastic paraparesis, with weakness of both lower extremities at approximately 4/5 strength. Deep tendon reflexes were brisk in all extremities, with ankle clonus in both legs. Babinski sings were bilaterally positive. He had paresthesia below the level of the T7-8 dermatome. Difficulty in micturition was noted. The patient had no sign of meningeal irritation. The results of his laboratory tests showed that his complete blood cell count, chemistry, immunoglobulin levels, C-reactive protein, erythrocyte sedimentation rate, and urinalysis were all within reference values. In particular, alterations in the liver function test results, suggestive of infectious mononucleosis, were not observed. Serological tests for syphilis, hepatitis B and C, HIV, and human T-lymphotropic virus type 1 were negative. The test results were also negative for anti-nuclear antibodies, anti-double stranded DNA, and cytoplasmic and perinuclear types of antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, and anti-aquaporin-4 antibody. Antibody titers were not elevated for herpes simplex virus immunoglobulin M (IgM), varicella zoster virus IgM, Epstein–Barr virus IgM, and CMV IgM. CMV IgG was found elevated significantly. Additionally, the tests for coxsackie A16 and enterovirus were not significantly elevated, although we could not perform a serodiagnosis with paired serum samples. A malignancy survey, in which contrast-enhanced CTs of the chest, abdomen, and pelvis were included, was conducted in the present patient, and no cancer was identified. Additionally, tumor markers (alpha-fetoprotein, CEA, CA19-9, and soluble interleukin-2 antigen) were all within normal ranges. Examination of CSF showed elevated white blood cells, although protein (34 mg/dl) and glucose (57 mg/dl) levels were within normal ranges. The CSF IgG index 0.8 was found to be mildly elevated. The myelin basic protein (40.0 pg/ml) levels were not increased, and there were no oligoclonal IgG bands in the CSF sample. Nerve conduction velocity studies of the peripheral nerves indicated that they were intact. Sensory evoked potentials obtained by tibial nerve stimulation demonstrated no reproducible waves. Both brain and spinal cord magnetic resonance images (MRI) obtained at admission appeared normal (Figs. , , and ). Brain and spinal cord MRI examinations with gadolinium-enhancement were also performed, although no significant enhancement was demonstrated. After admission, the patient’s weakness and deep sensation disturbance of the lower extremities progressively worsened. He was tentatively diagnosed with transverse myelitis, and treatment was started with intravenous methylprednisolone at a dose of 1000 mg/day for 3 days, followed by oral prednisolone (PSL) (60 mg/day). After 7 days, the muscle weakness in his lower extremities continued to worsen, and we added intravenous immunoglobulin therapy (IVIG) at a dose of 0.4 mg/kg for 5 days. Ten days after admission, intravenous administration of ganciclovir (600 mg/day, 19 days) was initiated because CMV DNA was found in his CSF following polymerase chain reaction analysis (PCR) performed at admission. The deterioration of his symptoms ceased, and the weakness in his lower extremities gradually recovered. Other findings in his CSF also improved, including the results for white blood cells (13/mm3; all cells were lymphocytes), protein (23 mg/dL), and glucose (62 mg/dL). The CSF samples were also negative for CMV. However, MRI performed again on day 26 after admission demonstrated a spinal cord lesion of high signal intensity at cervical levels C2–C6, suggesting that the spinal cord was involved and may have been responsible for the paraplegia, although his paraplegia continued to improve with treatment (Fig. ). Additionally, a hyperintense signal was observed in the right frontal subcortical white matter (Figs. and ). On day 40 after admission, the weakness and numbness of his lower extremities again worsened, and myoclonic movements appeared in his lower legs. Subsequently, a loss of finger dexterity appeared bilaterally. In addition, the patient developed dysarthria and truncal ataxia, the latter of which resulted in his inability to maintain a sitting position. Brain MR images demonstrated faint, irregular-shaped lesions involving cerebral white matter with dense T2-weighted and fluid attenuated inversion recovery (FLAIR) hyperintensities in the internal capsules, suggesting that extensive disseminated demyelination was actively ongoing (Figs. and ). The CSF examination results showed re-elevation of protein (39 mg/dL), and MBP (58.9 pg/mL) was also increased compared with results from the initial CSF study, although both levels were within normal ranges. The white blood cell count in the CSF did not increase (7/mm3). We considered the possibility that the patient had ADEM, and intravenous methylprednisolone (1000 mg/day, 3 days) was administered again, followed by IVIG (0.4 mg/kg, 5 days). After this treatment, his neurological deterioration ceased, but he had residual neurological sequelae. Time course of clinical symptoms, CSF results, treatment, and MRI findings in the present patient are schematically shown (Fig. ).
A 29 years-old man was admitted to our neurological department with five months of progressive disability in walking, paresthesia in the arms when bending the neck, numbness in the hands, and back pain. He had been treated for many years with aerosol salbutamol during exacerbations of asthma. Apart from periodic jaw spasms during the last five years, there were no apparent previous illnesses and no suspicion of infection within the last six months. During the last two years, he had been successfully treated for his injectable drug abuse with daily oral methadone. The patient had had negative hepatitis C virus RNA (HCV) serology two years before presentation. The neurological examination revealed positive Lhermitte`s sign, hypoesthesia in the hands, normal muscle strength in the upper limbs, reduced muscle strength in the legs (4 on a MRC scale), and reduced dorsiflexion of the feet (4 on a MRC scale). In addition, the patient had severe increased spasticity in the extensor muscles of the lower limbs, bilateral-positive Babinski, and a broad-based gait requiring support.\nSpinal cord MRI demonstrated extensive longitudinal spinal cord lesions from the cervical vertebral segment C1 to C5 and thoracic vertebral segment T2 to T11 (Figure ). The cervical lesion was located in the dorsal part and over a short distance in the lateral part on the right side on T2-weighted images. Discrete enhancement was found in the posterior part. Changes in the thoracic part were seen almost over the cord's entire cross section on the T2-weighted images, but enhancement was only demonstrated in the lateral part on both sides. The brain MRI was normal.\nA lumbar puncture was performed with cerebrospinal fluid showing slight pleocytosis with 11 mononuclear cells, a slightly increased protein to 0.64 g/l, normal IgG index and no oligoclonal bands, no antibodies against the varicella-zoster virus, herpes virus, entero-virus, or borrelia. The blood tests showed normal B12 vitamin, rheumatoid factor IgM and ANA, negative HIV serology, negative syphilis RPR, negative TB gamma interferon release assay, negative MOG- and AQP-4 antibodies, and increased ALAT to 200 U/l. Tests for HCV serology and HCV RNA were both positive.\nTreatment of HCV infection with Zepatier (elbasvir 50 mg and grazoprevir 100 mg) one tablet daily was initiated and continued for three months. Follow-up blood tests showed normalization of ALAT, negative HCV serology, and normalization of the spinal cord changes on MRI. The neurological findings were unchanged. There was no clinical suspicion of rheumatic, vascular or skin diseases and normal thyroid, white blood cells and renal function tests. With that condition, we found no indication for steroid treatment also taking into account previous episodes of psychosis in relation to his drug abuse.\nDespite a four-week course of inpatient rehabilitation, the physical condition was only slightly improved. Currently (two years later), walking distance is reduced, a stick is required when walking outside, and medication is still necessary for spasticity and neuropathic pain in the legs.