神經纖維瘤第一型神經激活表現變化之探討

Abstract

神經系統疾病神經纖維瘤第一型 (neurofibromatosis type1，NF1)的發生率約1/3000-4000為常見單一基因的體染色體顯性遺傳疾病。其外顯率100%，是一種進行性、持續性、變異性相當高的遺傳疾病。NF1約有1.3-2.3%神經病變症狀，且常有疼痛問題主訴。傳統的神經傳導檢查及肌電圖，對於膜電位的改變及神經的興奮性而言，無法提供相關的資訊。因此本實驗在於利用新的神經興奮傳導檢查儀器，來比較NF1與一般人臨床上神經膜電位的改變，及神經的興奮性變化，相關之研究。 神經興奮傳導檢查結果可分出(1) 刺激-反應曲線、(2) 強度 - 持續時間、(3) 閾值電緊張 、(4) 電流 - 電壓曲線 (5) 恢復週期。 在這項研究中，我們共收集神經纖維瘤第一型患者75人，正常對照組共計70 人。每位受試者評估5個項目，部位為正中神經，尺神經的感覺及運動神經及脛骨神經之運動神經。 我們發現在刺激-反應曲線和強度 - 持續時間實驗結果中，NF1與健康正常人相比正中神經之運動及感覺軸索及尺神經感覺神經軸索在(1)Stimulus for 50% max response所需電流量偏高，(2) Rheobase實驗結果中偏高。代表NF1病人的動作電位需要更大的刺激。可能推測的原因是NF1，有些神經束密度不同；又許旺細胞腫瘤的異常增生，導致髓鞘減少或是在某些區域髓鞘消失。 因此可能對paranode的快速鉀離子通道造成影響。 在閾值電緊張實驗結果中，尺神經之感覺神經在過極化方面有許多顯著差異，包含TEh(overshoot)偏低等。可能表示在此區域慢速K+增加，這個結果可能是因為Na+/K+ pump失去功能，造成傳導被抑制 。 在電流 - 電壓曲線實驗結果中，NF1與健康正常人的比較，正中神經之運動神經、尺神經之運動神經、脛骨神經之運動神經Hyperpolarization I/V slope皆向上偏，為外向整流(outward rectification) 的電流出現。NF1許旺細胞瘤的增生引起鉀通道被阻斷，導致NF1過極化現象比一般人明顯。 在恢復週期實驗結果中，NF1病人感覺神經Latency時間較短，是由時NF1產物neurofibromin易造成感覺神經元敏感，在神經傳導上可能導致發射間隔時間變少，可能讓神經纖維瘤第一型病人較容易感受到疼痛的感覺。 Refractoriness at 2.5ms尺神經之運動神經及正中神經之感覺神經閾值的改變百分比偏少，意謂著再產生動作電位的閾值較低。NF1在相對不反應期所需的刺激閾值較低，表示鈉離子通道的復活較一般人快。 神經纖維瘤第一型之神經病變的神經興奮性改變，仍未被仔細研究過，故經由神經興奮傳導檢查所得到的結果，提供給我們更多的訊息，在遺傳諮詢方面，可用來解釋為何神經纖維瘤第一型病患易感到疼痛麻刺感的有力證明，並期能提供未來臨床上的參考。

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder, affecting approximately one in every 4000 individuals. Although the penetrance rate for NF1 is 100%, the clinical features are highly variable among families as well as intra-family. It has been estimated that 1.3~2.3% of NF1 patients has neuropathic symptoms, and neuropathic pain is one of the common complaints. Traditional nerve conduction test and electromyography which is usually unremarkable in NF1 patients, cannot provide information such as changes in membrane potentials and nerve excitability. This study employed the newly developed nerve excitability test (NET) to compare the parameters of nerve membrane potential and axonal excitability between NF1 and healthy individuals. In this study, we have recruited 75 NF1 patients and 70 healthy individuals as normal controls. Every subject is evaluated in 5 individual nerves: median motor and sensory nerve, ulnar motor and sensory nerve, and tibial motor nerve. The results of the NET can be divided into 5 main categories: (1) SR, stimulation-response curve; (2) Strength-duration curve; (3) Threshold electrotonus; (4) Current-voltage curve; and (5) Recovery cycle. In the stimulation-response curve test, NF1 subjects had higher rheobase and higher current in stimulus for 50% max response in the motor axons of median nerve and the sensory one in both median and ulnar nerves. The reason might be due to different density of the nerve fascicles and dysmyelation of some nerve areas in NF1 patients, which could cause inactivation of the fast K+ channels at the paranodal region. In the threshold electrotonus test, NF1 subjects had lower TEh (overshoot) in the sensory axons of the ulnar nerve. This indicates an increase in slow K+ current and keep the axonal membrane in a hyperpolarization state which possibly reasults from the dysfunction of the Na+/K+ pump in the conduction block region. In the current-voltage curve test, the NF1 subjects had significantly higher Hyperpolarization I/V slope in the motor axons of the median, ulnar and tibial nerves compared to that of the controls. This might due to the increase of the outward rectification of the K+ current causing a slow polarizating effect. Proliferation of schwannoma cells in NF1 will cause increasing of K+ outward current and result in a more obvious hyperpolarization than healthy subjects. In the Recovery cycle test, compared to controls, the latency of the sensory axons in NF1 patients is conspicuously short rendering the high frequency of neuropathic pain in NF1 patients. The refractoriness at 2.5ms showed a significant low threshold in the motor axons of the ulnar and sensory ones in the median nerves of the NF1 subjects, indicating that the threshold to generate a new action potential is reduced. Concerning the threshold in RRP (relative refractory periods), NF1 patients had a significant low threshold comparing to that of controls suggesting the reactivation of the nodal Na+ channel is faster in NF1 patients than in healthy subjects. The nerve excitability change in NF1 neuropathy has not yet being well studied. The results from our study provide more information about the changes of the electrophysiological parameters in NF1 which will facilitate our understanding of the neuropathic pain in NF1.