吉良 潤一

基礎疾患なく雷鳴頭痛とposterior reversible encephalopathy syndrome（PRES）を発症し，経過中可逆性の脳血管攣縮をみとめた1例

A 56-year-old woman attended our hospital because of acute severe (thunderclap) headache. Neurological examination was normal and no abnormality was found on head CT or by cerebrospinal fluid examination. A few days later, she experienced a recurrence and suffered a seizure in her left upper and lower extremities. On neurological examination, she had conjugate deviation of the eyes toward the right side and left lower limb paralysis with Chaddock sign. MRI showed multiple hyperintense lesions in the bilateral occipital and parietal lobes, predominantly in the subcortical white matter at the right side on T2-weighted and FLAIR images. We diagnosed posterior reversible encephalopathy syndrome (PRES) because the ADC map showed a vasogenic edema pattern (increased ADC values in the hypodense lesions on diffusion-weighted image). Her blood pressure was normal and there were no underling diseases. As MRA showed vasoconstriction especially in bilateral posterior cerebral arteries, we initiated a therapy with a Ca-channel blocker. On follow-up MRI, the hyperintense lesions on T2-weighted and FLAIR images had almost disappeared, and vasoconstriction was also improved on MRA. This case suggested that cerebral vasoconstriction could underlie both thunderclap headache and PRES.

副交感神経障害を主徴としたMPZ遺伝子変異Thr124MetによるCharcot-Marie-Tooth病の1例

Erectile dysfunction, dysuria, photophobia, and chronic cough developed insidiously in a 49-year-old man from his third decade. Severe difficulty of urination resulted in intermittent catheterization. He had six family members who had suffered similar autonomic symptoms with or without motor deficits. He presented asymmetrical tonic pupils, a neurogenic bladder, and mild sensory impairment in the distal parts of the bilateral lower limbs without orthostatic hypotension and motor deficits. Nerve conduction studies revealed mild axonal changes with slightly reduced conduction velocities in the lower limbs. His left pupil over-responded to instillation with 0.125% pilocarpine. Functional bladder tests showed an atonic bladder, suggesting postganglionic parasympathetic involvement. Autonomic evaluation for sympathetic components including head-up tilt, beat to beat responses to Valsalvas maneuver, cardiac MIBG imaging, plasma catecholamine levels and sweat tests were all normal. A genetic test disclosed a heterozygous mutation of myelin protein zero (MPZ); p.Thr124Met. Selectively distributed dysautonomia in this pedigree may indicate parasympathetic postganglionic components including the ganglion as the primary target of this mutated MPZ in the autonomic nervous system.

Education Program 3 多発性硬化症の臨床研究の最近の進歩：アストロサイトパチーからみた脱髄

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. Recently, a specific IgG against NMO, designated NMO-IgG, was discovered, and the relevant antigen was found to be aquaporin 4 (AQP4), one of the major water channel proteins in the CNS. The sensitivity of NMO-IgG/anti-AQP4 antibodies for NMO varies from 30% to 80%, while specificity is 90-100%. Pathological studies on NMO patients have revealed perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions, while myelin basic protein (MBP) staining was relatively preserved. IgG from NMO-IgG-seropositive NMO patients induces astrocyte death in culture in the presence of complement, and reproduces astrocyte loss in vivo when MBP-specific T cells are co-transferred to cause experimental autoimmune encephalomyelitis. Therefore, it is postulated that the complement-activating anti-AQP4 antibodies have a pivotal role in the development of NMO lesions through astrocyte necrosis, and that demyelination is a secondary event. Balós disease is characterized by alternating rings of demyelination and preserved myelin. As additional MS-like lesions often coexist in Balós cases, Balós disease is regarded as a variant of MS. However, Balós concentric rings are also observed in NMO cases and in Asian opticospinal MS patients in the cerebral white matter, spinal cord and optic chiasm. In demyelinated areas, many hypertrophic astrocytes are present, in close contact with oligodendrocytes that often show apoptotic features. In the outermost layer of preserved myelin, stress proteins involved in tissue preconditioning are abundant in oligodendrocytes. The peri-plaque white matter is thus assumed resistant to subsequent attack, thereby leaving a layer of preserved myelin. In some patients, Balós concentric rings develop systematically in a centrifugal direction, while other patients show simultaneous enhancement of multiple rings. Therefore, tissue preconditioning and successive ring formation does not fully explain the mechanism of the disease. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of all actively demyelinating lesions in four Filipino Balós patients. None of six other patients with magnetic resonance imaging-confirmed Balós disease was seropositive for anti-AQP4 antibodies. I therefore propose that AQP4 astrocytopathy, in the absence of anti-AQP4 antibodies, is characteristic of Balós disease. Since a similar loss of AQP4 without perivascular deposition of immunoglobulin and complement is also observed in autopsied CNS tissues from NMO and MS cases, I consider that autoantibody-independent astrocytopathy may widely occur in human CNS demyelinating diseases, including Balós disease, MS and NMO.