Denervation Supersensitivity Research Articles

Ophthalmic effects of Bitis atropos (Berg Adder) envenomation

Objective: Bitis atropos, commonly known as the Berg Adder, is a venomous viperid found in Southern Africa. Envenomation is rare, with reported cases primarily exhibiting cytotoxic, neurotoxic, and myotoxic effects, including severe systemic manifestations and ophthalmologic complications such as ptosis, mydriasis, and loss of accommodation. However, the underlying pathophysiology of these sequelae remains poorly understood. Case: We present the case of a 26-year-old male who suffered severe envenomation by a Berg Adder in the Limpopo Province, South Africa. Within minutes of the bite, the patient experienced hypoesthesia, progressive dyspnea, and loss of consciousness, followed by prolonged intensive care management. Ophthalmic examination revealed bilateral dilated pupils, right ptosis, and impaired accommodation, alongside generalized muscle weakness, anosmia, ageusia, and dysphagia. Despite the absence of antivenom, the patient’s condition showed gradual improvement over a 127-day follow-up period. Notably, the pupils exhibited denervation supersensitivity, similar to Adie’s tonic pupil, and responded well to low-dose pilocarpine. Conclusion: The clinical features observed, particularly the ophthalmoplegic triad, can be attributed to the effects of phospholipase A2 proteins in the venom, which disrupt cholinergic transmission at muscarinic receptors. This case underscores the complexity of Berg Adder envenomation and highlights the variability in recovery timelines for different neuro-ophthalmic effects. This case provides valuable insights into the pathophysiology and management of severe Berg Adder envenomation, emphasizing the role of targeted therapeutic interventions such as pilocarpine in mitigating long-term sequelae.

The Neuroanatomical Basis of the 5-HT Syndrome and Harmalineinduced Tremor.

The 5-HT syndrome in rats is composed of head weaving, body shaking, forepaw treading, flat body posture, hindlimb abduction, and Straub tail. The importance of the brainstem and spinal cord for the syndrome is underlined by findings of 5,7-dihydroxytryptamine (5,7-DHT)-induced denervation supersensitivity in response to 5-HT-stimulant drugs. For head weaving and Straub tail, supersensitivity occurred when the neurotoxin was injected into the cisterna magna or spinal cord, for forepaw treading in cisterna magna, and for hindlimb abduction in the spinal cord. Although 5,7- DHT-related body shaking increased in the spinal cord, the sign decreased when injected into the striatum, indicating the modulatory influence of the basal ganglia. Further details on body shaking are provided by its reduced response to harmaline after 5-HT depletion caused by intraventricular 5,7-DHT, electrolytic lesions of the medial or dorsal raphe, and lesions of the inferior olive caused by systemic injection of 3-acetylpyridine along with those found in Agtpbp1pcd or nr cerebellar mouse mutants. Yet the influence of the climbing fiber pathway on other signs of the 5-HT syndrome remains to be determined.

Severe blood pressure elevation following ephedrine administration during carotid endarterectomy under general anesthesia: A CARE-compliant case report.

During carotid endarterectomy (CEA) surgery, blood pressure management is particularly important to prevent cerebrovascular and cardiac complications. Ephedrine is a commonly used vasopressor, however, we report the case of a patient with unusually severe blood pressure elevation following intravenous ephedrine administration during CEA. A 72-year-old man diagnosed with right proximal internal carotid artery stenosis underwent CEA under general anesthesia. After declamping the common carotid artery, blood pressure rapidly increased by 125 mm Hg (from 90 to 215 mm Hg) after ephedrine (4 mg) was administered, but the heart rate was stable. There was an ordinal increase in blood pressure after the same small dose of ephedrine was administered at the early stage of the surgery. And the surgical approach was difficult because he had a high location of carotid bifurcation and a prominent mandibular angle. Because of the anatomical proximity of the cervical sympathetic trunk to the carotid bifurcation and the particularly complicated surgical process in the present case, we postulate the reason for this adverse reaction as transient sympathetic denervation supersensitivity. Perdipine (0.5 mg) was administered repeatedly to reduce blood pressure. After surgery, he was diagnosed with right hypoglossal nerve palsy, and no other abnormal signs were found. This case highlights the need for caution in the use of ephedrine, which is commonly used in CEA surgery, wherein blood pressure management is particularly important. Although it is a rare and unpredictable case, α-agonists are considered safer in situations where sympathetic supersensitivity is possible.

Dilute pilocarpine test for diagnosis of Adie\u2019s tonic pupil

We have compared the diagnostic ability of different concentrations of 0.125% and 0.0625% dilute pilocarpine for detecting denervation supersensitivity in unilateral Adie’s tonic pupil. This retrospective, observational, case–control study involved 117 subjects, consisting of 56 patients with unilateral Adie’s tonic pupil and 61 controls with other causes of unilateral dilated pupils. Subjects underwent the dilute pilocarpine test with one of the two concentrations, 0.125% or 0.0625%. Pupillary light reflex was recorded with a dynamic pupillometer at baseline and at 30–40 min after instilling one of the two concentrations of dilute pilocarpine. Diagnostic accuracy of two different concentrations of the dilute pilocarpine test, 0.125% group versus 0.0625% group, were compared by area under the receiver operating characteristic curve (AUC). Diagnostic ability of the dilute pilocarpine test for detecting denervation supersensitivity in unilateral Adie’s tonic pupil was significantly better in the 0.0625% group than in the 0.125% group (AUC = 0.954 vs. 0.840, respectively, P = 0.047). In the 0.0625% group, the change in maximal pupil diameter of ≥ 0.5 mm after topical pilocarpine instillation showed 100% sensitivity and 82.8% specificity for detecting Adie’s tonic pupil. This study confirmed that pupillary constriction with 0.0625% pilocarpine is better than 0.125% pilocarpine for detecting denervation supersensitivity in Adie’s tonic pupil. Digital pupillometry is a reliable method for assessing denervation supersensitivity in Adie's tonic pupil.

Ophthalmic and Neuro-ophthalmic Manifestations of Coronavirus Disease 2019 (COVID-19)

ABSTRACT Purpose To describe a case of inflammatory chorioretinopathy and Adie’s syndrome possibly associated with COVID-19. Methods Observational case report. Results A 51-year-old woman developed fever, cough, and headache followed by retro-ocular pain and reading impairment. She tested positive for SARS-COV-2 infection by qualitative real-time reverse-transcriptase-polymerase-chain-reaction. The slit-lamp and funduscopic exam revealed abnormal pupillary response and yellowish creamy deep chorioretinal lesions, which were not present in previous examinations. Instillation of pilocarpine demonstrated denervation supersensitivity, and it was suggestive of bilateral Adie tonic pupil. A comprehensive work-up ruled out other systemic, autoimmune, or infectious diseases. Conclusions This case illustrates the possible association between multifocal chorioretinitis and Adie’s syndrome, and the SARS-COV-2 infection in humans. Further investigation of virus infectivity specifically within ocular tissues has to be conducted.

Obituary: Sir Roger Bannister (1929–2018)

Obituary: Sir Roger Bannister (1929–2018)

Unusually large ephedrine-induced blood pressure increases due to cardiac sympathetic denervation supersensitivity in a patient with Parkinson\u2019s disease

BackgroundParkinson’s disease (PD) patients often suffer from cardiac sympathetic denervation, a hallmark of which is orthostatic hypotension. Denervation supersensitivity to sympathomimetic drugs is also seen in such patients, and this phenomenon is important and can be sometimes dangerous.Case presentationA 65-year-old male underwent gastrojejunostomy. The patient had severe PD and did not exhibit metaiodobenzylguanidine (MIBG) accumulation in his heart, which was indicative of cardiac sympathetic nerve denervation. When 8 mg of ephedrine was administered intravenously, an unexpectedly large increase in blood pressure was observed. The phenomenon recurred when 4 mg of ephedrine was administered again, and nicardipine was required to suppress the patient’s blood pressure.ConclusionsDenervation supersensitivity is not as well recognized as other complications seen in PD patients, but anesthesiologists should be aware of it because sympathomimetic drugs can have excessively strong effects in patients with the condition.

Author response: Teaching Video NeuroImages: Olivary enlargement and pharyngeal nystagmus.

We appreciate the comments made by Dr. Bhattacharjee regarding our Teaching Video NeuroImage.1 The cavernoma was an incidental feature on the brain CT conducted after the patient had a fall, and mild hypertrophy olivary degeneration (HOD) was already visible on the subsequent MRI. However, the palatal tremor (PT) was not diagnosed until 36 months after the first studies. Here, PT and HOD are the manifestation of denervation supersensitivity, secondary to lesions involving the unilateral supraolivary central tegmental tract (CTT). According to the anatomical and radiologic changes in HOD, the MRI would likely not detect pseudohypertrophy early on or after a substantial time following Mollaret triangle injury.2

Tourette Syndrome: Clinical Features and Pathophysiology

Tourette syndrome (TS) is a neuropsychiatric disorder with the onset in childhood. TS is a form of tic disorders, and characterized by the motor and vocal tics, and comorbidities such as attention deficit hyperkinetic and obsessive compulsive disorders. These symptoms appear age dependently, showing a wax and wane course, and subside or abolish by the late teens. Pathophysiology of TS involves the dysfunction of both motor and non-motor basal ganglia-thalamo-cortical circuitries. The nigrostriatal dopamine (DA) system takes the exponential decrement at the striatum. In TS, this decrement is accelerated in association with DA-D2 receptor super-sensitivity, which disinhibits the descending and ascending output pathways of the basal ganglia. Disinhibited motor basal ganglia-thalamo-cortical circuitries develop the specific tics according to the target sites. Hypofunction of the 5-hydroxytriptophan (5-HT) neurons of the brainstem innervate the striatum involved in non-motor basal ganglia-thalamo-cortical circuitries and cause the obsessive compalsive disorder and other behavioral disorders. The associated DA-D2 receptor supersensitivity is assumed to be a consequence of the developmental abnormalities and not due to denervation supersensitivity. The treatments of TS aim to correct the 5-HT hypofunction by improving the environmental factors and super-sensitized DA receptors medically by a small dose of levodopa and/or aripiprazole.

Differential effects of dopaminergic drugs on spontaneous motor activity in the common marmoset following pretreatment with a bilateral brain infusion of 6-hydroxydopamine.

The differential effects of dopaminergic drugs with different pharmacological profiles were investigated with respect to spontaneous motor activity in the common marmoset following pretreatment with a bilateral brain infusion of 6-hydroxydopamine (6-OHDA). Three marmosets received infusions of 6-OHDA (either 30 or 40 μg/side) into the bilateral dopamine-rich area running from the substantia nigra to the striatum. The motor activity of the 6-OHDA marmosets was compared with that of three intact marmosets. Following the administration of apomorphine (0.5 and 1 mg/kg, subcutaneously), the 6-OHDA group showed a tendency toward a brief increase in activity counts, suggesting denervation supersensitivity at the dopamine receptors. After the administration of methamphetamine (1 and 2 mg/kg, subcutaneously), the 6-OHDA group showed a significant decrease in activity counts, indicating limited dopamine release from the degenerated neurons. After the administration of l-3,4-dihydroxyphenylalanine (10 and 20 mg/kg, orally), the 6-OHDA group showed a significant increase in activity counts without hyperexcitation, consistent with the contribution of exogenous l-3,4-dihydroxyphenylalanine toward dopamine synthesis in the degenerated neurons. The present findings indicate that bilateral brain infusion of 6-OHDA in the marmoset may have preclinical utility as a primate model for investigating the behavioral properties of dopaminergic drugs in brains with dopaminergic neural deficits.

Autonomic components of Complex Regional Pain Syndrome (CRPS) are favourably affected by Electrical Twitch-Obtaining Intramuscular Stimulation (ETOIMS): effects on blood pressure and heart rate

IntroductionFavourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS).AimTo document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome...

American football and other sports injuries may cause migraine/persistent pain decades later and can be treated successfully with electrical twitch-obtaining intramuscular stimulation (ETOIMS)

IntroductionAutonomous twitch elicitation at myofascial trigger points from spondylotic radiculopathies-induced denervation supersensitivity can provide favourable pain relief using electrical twitch-obtaining intramuscular stimulation (ETOIMS).AimTo provide objective evidence that ETOIMS is safe...

Renal denervation and hypertension - The need to investigate unintended effects and neural control of the human kidney

Increased renal sympathetic nerve activity (RSNA) is present in human and experimental forms of arterial hypertension. Experimental denervation studies showed that renal nerves contribute to the development of hypertension. Clinical trials provided equivocal results on the antihypertensive efficacy of renal denervation in patients spurring discussions on technical aspects of renal denervation and further research on the role of renal nerves for the regulation of kidney function as well as the pathophysiology of hypertension. This review summarizes recent findings on adrenoceptor expression and function in the human kidney, adrenoceptor-dependent regulation of sodium chloride transport in the distal nephron, experimental data on chronic RSNA and the development of high arterial pressure and consequences of renal denervation that may limit its antihypertensive efficacy. Future research needs to reduce the gap between our knowledge on neural control of renal function in animals vs. humans to facilitate translation of experimental animal data to humans. More experimental studies on the temporal relationship between RSNA and arterial pressure in the chronic setting are needed to better define the pathogenetic role of heightened RSNA in different forms of arterial hypertension in order to improve the rational basis for renal denervation in antihypertensive therapy. Finally, research on unintended consequences of renal denervation including but not limited to reinnervation and denervation supersensitivity needs to be intensified to further assess the potential of renal denervation to slow the progression of renal disease and hypertension.

Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats

Parkinson’s disease (PD) is mainly characterized by motor signals. However, non-motor signals also affect and decrease the quality of life of PD patients. Among these non-motor signs are cardiovascular disorders as orthostatic hypotension, postprandial hypotension and cardiac arrhythmias, which may be due to the involvement of both central nervous system and peripheral autonomic nervous system. In the present study we investigated the cardiovascular function, evaluating cardiovascular reflexes (chemoreflex and baroreflex), in an animal model of Parkinsonism induced by bilateral infusion of the toxin 6-hydroxydopamine (6-OHDA), in the substantia nigra pars compacta (SNpc). The results showed that the animals induced to Parkinsonism had lower arterial pressure (AP) and heart rate HR) compared to control animals. We showed that after activation of the baroreceptors by phenylephrine (Phe) and sodium nitroprusside (SNP), the baroreflex sensitivity index was not changed between the groups. However, there was a greater increase in the AP when stimulated with Phe and greater tachycardia when stimulated with SNP in 6-OHDA animals. After activation of the peripheral chemoreceptors through KCN injection (cytotoxic hypoxia), there was a higher increase in pressor and bradycardic response in injured animals with bilateral 6-OHDA. These changes in the cardiovascular reflexes may be important adjustments mechanisms to maintain the cerebral blood flow in those animals, and may be a result of denervation supersensitivity to catecholamines in autonomic targets.

GHB for cataplexy: Possible mode of action.

The sleep disorder narcolepsy is caused by the loss of orexinergic neurones in the lateral hypothalamus. A troublesome symptom of narcolepsy is cataplexy, the sudden loss of muscle tone in response to strong emotions. It can be alleviated by antidepressants and sodium oxybate (γ-hydroxybutyric acid (GHB)). It is likely that the noradrenergic nucleus locus coeruleus (LC) is involved since it is essential for the maintenance of muscle tone, and ceases to fire during cataplectic attacks. Furthermore, alpha-2 adrenoceptors proliferate in the LC in cataplexy, probably due to 'heterologous denervation supersensitivity' resulting from the loss/weakening of the orexinergic input to the LC. This would lead to the sensitization of the autoinhibition mechanism of LC neurones mediated by inhibitory alpha-2 adrenoceptors ('autoreceptors'). Thus the excitatory input from the amygdala to the LC, activated by an emotional stimulus, would lead to the 'switching off' of LC activity via the supersensitive auto-inhibition mechanism. GHB is an agonist at both γ-aminobutyric acid (GABA) GABA (B) and GHB receptors that may be a subtype of an extrasynaptic GABA(A) receptor. GHB may prevent a cataplectic attack by dampening the tone of LC neurones via the stimulation of inhibitory extrasynaptic GABA receptors in the LC, and thus increasing the threshold for autoinhibition.

除神経過敏へのノルアドレナリン投与で心室頻拍をきたした重症パーキンソン病の1例

パーキンソン病（Parkinson's disease, PD） は自律神経症状を合併する多系統変性疾患である。近年，心臓交感神経の除神経過敏が証明されたが，PDの血管作動薬使用については十分に理解されていない。症例は78歳，男性。強い下腹部痛，発熱を主訴に搬送された。偽性腸閉塞に伴う敗血症性ショックと診断し，経肛門ドレナージ，輸液，抗菌薬投与を行った。しかし，徐々に血圧が低下したためノルアドレナリン（noradrenaline, NA）投与を開始した。直後から心室性期外収縮が頻発し，NA増量に伴い心室頻拍となり，さらに血圧が低下した。NAからバゾプレッシン（vasopressin, VP）に変更したところ，不整脈は著明に減少し，ショックから離脱できた。PDでは早期から心臓交感神経が障害される。除神経過敏を合併するPDでは，アドレナリン受容体を介さないVPへの早期変更を考慮すべきと考える。

パーキンソン病の心臓交感神経除神経過敏

パーキンソン病の心臓交感神経除神経過敏

Serotonergic transmission after spinal cord injury.

Changes in descending serotonergic innervation of spinal neural activity have been implicated in symptoms of paralysis, spasticity, sensory disturbances and pain following spinal cord injury (SCI). Serotonergic neurons possess an enhanced ability to regenerate or sprout after many types of injury, including SCI. Current research suggests that serotonine (5-HT) release within the ventral horn of the spinal cord plays a critical role in motor function, and activation of 5-HT receptors mediates locomotor control. 5-HT originating from the brain stem inhibits sensory afferent transmission and associated spinal reflexes; by abolishing 5-HT innervation SCI leads to a disinhibition of sensory transmission. 5-HT denervation supersensitivity is one of the key mechanisms underlying the increased motoneuron excitability that occurs after SCI, and this hyperexcitability has been demonstrated to underlie the pathogenesis of spasticity after SCI. Moreover, emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. There are functional relevant connections between the descending serotonergic system from the rostral ventromedial medulla in the brainstem, the 5-HT receptors in the spinal dorsal horn, and the descending pain facilitation after tissue and nerve injury. This narrative review focussed on the most important studies that have investigated the above-mentioned effects of impaired 5-HT-transmission in humans after SCI. We also briefly discussed the promising therapeutical approaches with serotonergic drugs, monoclonal antibodies and intraspinal cell transplantation.

Bedside test for anisocoria: Not a small matter.

Sir, The article by Chaudhry et al. is indeed interesting.[1] An abnormal dilated pupil in a critically ill patient could be alarming to the treating physician, even though anisocoria is not a dangerous adverse effect of ipratropium bromide, the condition may be misinterpreted as a severe neurologic emergency, since the patient is often sedated, paralyzed or has an altered mental status.[2] Though neuroimaging remains the most effective method to rule out the structural causes of acute anisocoria, we would like to suggest a simple bedside test to differentiate it from local cause. At the bedside, instillation of pilocarpine eye drops can be used to differentiate the anticholinergic drug effects from other causes of an abnormally dilated pupil as it is a directly acting parasympathomimetic agent, which duplicates the actions of acetylcholine and cause constriction of the pupil by stimulating the sphincter pupillae and altering accommodation by contracting the ciliary muscles.[3] With a lower concentration of 0.125% pilocarpine, a tonic pupil will constrict significantly more than the unaffected pupil because of the denervation supersensitivity. In case of ipratropium bromide induced mydriasis, the affected eye will be unresponsive to the ocular instillation of 1% pilocarpine, while the unaffected eye will constrict. On the contrary, pupillary dilation due to third nerve compression the pupil will still constrict with pilocarpine, since the sphincter muscle is still intact and responsive to cholinergic stimulation.[4] However, pilocarpine may also cause miosis, ciliary spasm, blurred vision, and photophobia. Unilateral mydriasis in an unconscious patient is an important clinical sign and differential diagnosis must be quickly performed in order to rule out structural and pharmacological causes.[5] Size of the pupil and its reaction to light at the bedside aid to assess the status and a pilocarpine eye-drop test helps to avoid unnecessary tests or decide further course of action.

Lack of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2): Consequences for mouse bladder development and function

To describe the morphological and functional consequences for bladder development and function when nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is lacking or reduced. The Bloated Bladder (Blad) mouse, lacking Nmnat2, and heterozygotes were utilized for this investigation. Morphology and development of the bladder were studied using immunohistochemistry against urothelial, smooth muscle, and nerve markers. Functional effects were assessed by organ bath experiments and cystometry. Homozygote mutants were malformed and died at birth, whereas heterozygotes survived and morphologically did not differ from wild-type controls. Morphological bladder changes appeared in the Blad mutants as early as embryonic day 15.5 (E15.5) with an extremely distended bladder at E18.5. Staining revealed that all the bladder layers were present and expressed mature markers in all three genotypes. No nerves could be demonstrated by immunohistochemistry in the Blad mutant bladder at E18.5. Organ bath analysis showed that bladders from Blad mutant showed signs of denervation supersensitivity in response to carbachol, and no response to electrical stimulation of nerves at E18.5. Adult heterozygotes, which have a reduced expression of Nmnat2 at E18.5, showed decreased responses to carbachol and electrical stimulation compared to wild-type controls. The latter also retained their ability to empty their bladders, but showed increased micturition pressures compared to controls. Complete loss of Nmnat2 leads to a mature but distended bladder in utero and is not compatible with survival. Moderate loss of Nmnat2 has no effect on bladder development, survival, and has only modest effects on bladder function later in life.