Clinical consequences of reinnervation disorders after focal peripheral nerve lesions

Clinical Neurophysiology 122 (2011) 219–228

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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Invited Review

Clinical consequences of reinnervation disorders after focal peripheral nerve lesions Josep Valls-Sole a,*, Carlos David Castillo a, Jordi Casanova-Molla a, Joao Costa b a b

Department of Neurology, Hospital Clínic, Universitat de Barcelona, IDIBAPS (Institut d’Investigació Biomèdica August Pi i Sunyer), Spain Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal

a r t i c l e

i n f o

Article history: Accepted 28 June 2010 Available online 24 July 2010 Keywords: Focal nerve lesions Reinnervation errors Motor control Compensatory activity

a b s t r a c t Axonal regeneration and organ reinnervation are the necessary steps for functional recovery after a nerve lesion. However, these processes are frequently accompanied by collateral events that may not be beneficial, such as: (1) Uncontrolled branching of growing axons at the lesion site. (2) Misdirection of axons and target organ reinnervation errors, (3) Enhancement of excitability of the parent neuron, and (4) Compensatory activity in non-damaged nerves. Each one of those possible problems or a combination of them can be the underlying pathophysiological mechanism for some clinical conditions seen as a consequence of a nerve lesion. Reinnervation-related motor disorders are more likely to occur with lesions affecting nerves which innervate muscles with antagonistic functions, such as the facial, the laryngeal and the ulnar nerves. Motor disorders are better demonstrated than sensory disturbances, which might follow similar patterns. In some instances, the available examination methods give only scarce evidence for the positive diagnosis of reinnervation-related disorders in humans and the diagnosis of such condition can only be based on clinical observation. Whatever the lesion, though, the restitution of complex functions such as fine motor control and sensory discrimination would require not only a successful regeneration process but also a central nervous system reorganization in order to integrate the newly formed peripheral nerve structure into the prepared motor programs and sensory patterns. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of axonal regeneration and reinnervation process. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Excessive axonal branching in the regenerating nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Misdirection of axons and target organ reinnervation errors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neuronal and axonal excitability enhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Reinnervation activity in non-injured nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical syndromes derived from abnormalities in the reinnervation process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Postparalytic facial syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reinnervation-related laryngeal disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Abnormal hand and finger movements after ulnar nerve lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Compensatory hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Human peripheral nerve trunks are susceptible to various types of injuries. Traumatisms, compression, entrapment and ischemia

* Corresponding author. Address: EMG Unit, Neurology Department, Hospital Clínic, Villarroel, 170, Barcelona 08036, Spain. Tel.: +34 932275413; fax: +34 932275783. E-mail address: [email protected] (J. Valls-Sole).

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are among the most frequent causes of damage. Traumatic and ischemic lesions present usually with an acute phase of loss of motor, sensory and autonomic function, while compression and entrapment are lesions manifesting with more slowly presenting symptoms, allowing for some adaptation to occur. The degree of nerve lesion severity (Sunderland, 1978) is obviously related to the prognosis (Lee and Wolfe, 2000). However, functional impairment at outcome does not only depend on the severity of the lesion but also on the many problems that accompany the reinnervation

1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.06.024

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process that typically follows axonal degeneration. Unfortunately, though, success of the reinnervation process is not guaranteed neither by nature nor by currently available interventional procedures. Nerve regeneration requires sprouting of new axons, which may grow to reinnervate the target organ if the medium is appropriate. Several problems may present during this process: the axons may fail to find their way, the medium may be hostile and the target organ might have become incompetent when it receives the growing axon (Borisov et al., 2001). If reinnervation fails, the logical consequence is functional deficit, implying mainly paresis and hyposthesia. However, even if the target organ has maintained a good functional state up to the time when it receives the reinnervating axons, other problems may arise because of abnormalities in the reinnervation process. In this case, the typical problem is hyperactivity, instead of functional deficit, which reveals typically as muscle spasms and dysesthesia. The most widely known abnormality in the reinnervation process is that axons may be misdirected to targets different from those that were previously innervating. This is accompanied by other abnormalities in the peripheral nervous system, such as unnecessary branching of axons, axonal growing in distant nerves, compensatory hyperactivity in non-damaged territories and unwanted increase in excitability of the parent neurons. Apart from that, peripheral nerve lesions trigger plastic changes in the central nervous system, which are not in the scope of this review. There is only scarce evidence for the positive diagnosis of reinnervation-related disorders in humans. Indeed, although they are known to be the substrate of a few disturbing clinical manifestations (i.e., synkinesis after peripheral facial nerve palsy), their exact contribution to the pathophysiology of other syndromes featuring motor, sensory and autonomic dysfunctions is unknown. Electrophysiological studies are likely to provide only weak arguments for the diagnosis of disorders of reinnervation. In many instances, it may be difficult to relate the abnormalities found in the electrodiagnostic studies with clinical manifestations that might originate from plastic or adaptive changes. At present, we can only speculate on the interpretation of some clinical phenomena. This review deals with the pathophysiological peripheral nerve processes underlying reinnervation-related disorders and the clinical and electrophysiological characteristics of the most common conditions that can be attributed to abnormalities in the process of reinnervation after a focal peripheral nerve lesion: postparalytic facial syndrome, vocal cord disorders after laryngeal nerve neuropathies, peripheral (pseudodystonic) movement disorders after ulnar nerve neuropathy and axial hyperhidrosis as a manifestation of compensatory sweating. 2. Pathophysiology of axonal regeneration and reinnervation process After a nerve lesion, both the axotomized segment and the parent neuron undergo morphological and metabolic changes that can be considered the first step in the process of reinnervation. However, at the same time troubles with the reinnervation process begin, which will hamper a successful functional recovery. We considered the following adverse possibilities: (1) Uncontrolled branching of growing axons at the lesion site. (2) Misdirection of axons and target organ reinnervation errors, (3) Enhancement of excitability of the parent neuron, and (4) Compensatory activity in non-damaged nerves. The importance and relative weight of these problems in the pathophysiology of clinical symptoms varies according to individuals and may depend on the injured nerve. Whatever the lesion, though, the restitution of complex functions such as fine motor control and sensory discrimination would require not only a successful regeneration process but also a central nervous system reorganization in order to integrate the newly

formed peripheral nerve structure (Lundborg et al., 1994; Navarro et al., 2007). 2.1. Excessive axonal branching in the regenerating nerve Axonal growth begins with the appearance of axon cones that emerge from proximal stumps, elongating within the Büngner bands. These are a cluster of Schwann cells enclosed around the basement membrane. The proximal stump emits many axonal sprouts that try to go across the non-friendly scar tissue of the injury site. Some of them grow in various directions, unable to find their way into the Büngner bands (or the Büngner bands have become too old and no longer viable) and end up curling over themselves to form a neuroma. Those that succeed in reaching an endoneurial tube and newly formed Schwann cells may proceed towards a target at a rate of approximately 1 mm/day (Seddon et al., 1943). Several sprouts may grow at the same time, with many axons competing for the available funicula. At target organ level, the growing axons will compete for innervation, which will lead to loss of the pre-lesional innervation selectivity. In the motor domain, the structure of the motor unit will be modified. Muscle fibres that were previously belonging to a specific motor unit will likely be innervated by more than one motor axon, or a newly formed axonal sprout will connect with a number of muscle fibres that were previously innervated by different axons. The change in the structure of the motor unit will have functional significance, generating a mismatch between central commands to motor neurons and the actual distribution of muscle fibres innervated by those motor neurons (Monti et al., 2001). Such mismatch could be the basis of some sensorimotor disturbances, such as synkinetic movements. Although, theoretically, the structure of the motor unit can be further modified by prunning, the extent of it and its benefit for motor unit functioning in humans is presently unknown. The structure of the motor unit is undoubtedly reflected in motor unit action potentials recorded with electromyography (EMG). However, the techniques nowadays available are still far from allowing reproducible identification of the recorded muscle fibres and motor units (Zalewska and Hausmanowa-Petrusewicz, 2008; Gazzoni et al., 2004). The EMG recording of motor unit action potentials is determined by the existent motor units and no distinction can be made of whether a specific muscle fibre was once belonging to the same motor unit or has been recruited after collateral reinnervation from another motor unit. Excessive branching in a motor nerve will lead to an increase in the probability to find late responses (A waves) during the study of the F wave. These are action potentials that appear at a latency incompatible with a motoneuron mediated response and, therefore, are generated along the nerve, likely in a site where the lesion has caused either ephaptic transmission or axonal branching (Roth, 1993; Navarro, 2009). However, the presence of A waves cannot be taken as necessarily indicative of a peripheral nerve lesion because they can also be found in healthy subjects, mostly in lower-extremity nerves (Puksa et al., 2003). A similar situation may occur in the sensory units although having evidence for that is still more difficult to obtain than for the motor units. 2.2. Misdirection of axons and target organ reinnervation errors The axons that succeed in finding their way through the endoneurial tube will eventually reach a target organ. Unfortunately, however, that target organ may not be the same as the one that the parent neuron was innervating before the lesion. An erroneous reinnervation of a muscle fibre within the same muscle may cause some trouble (Monti et al., 2001) but reinnervation errors can go beyond the muscle previously innervated, involving muscle fibres

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of other muscles. This can be a significant problem with nerves innervating muscles with antagonistic functions. In these cases, reinnervation errors could be responsible for co-contraction when reciprocal inhibition is needed (Madison et al., 1996; Valero-Cabré and Navarro, 2002). A natural source of such errors comes in lesions rostral to nerve branching points. If axons are misdirected, they can follow a nerve collateral leading to a different muscle from the one previously innervated. This type of abnormal reinnervation is not exclusive of motor axons. It might well be that axons take a direction towards a nerve branch that ends up in sensory endings (Navarro, 2009). It is unknown if such motor axonal terminations in sensory endings have any function but they certainly compete with axons following the appropriate course. After such midirected reinnervation, some prunning may take place (Brushart et al., 1998; Redett et al., 2005), but again the extent and benefit of such prunning in human subjects is unknown at present. Electromyographic evaluation may readily show the abnormal cutaneous reinnervation by motor axons. Montserrat and Benito (1990) recorded muscle action potentials to stimulation of cutaneous branches of mixed nerves, a finding that was attributed to an axon reflex or to an ephatic connection in the site of injury. These abnormal responses were seen for various years after the lesion, suggesting that they were the consequence of rather stable connections. 2.3. Neuronal and axonal excitability enhancement Axonal damage triggers a series of morphological and functional changes in the cell body, which modifies its phenotype from a transmitter to a regenerative mode, activating molecular pathways that promote neuronal survival and axonal regeneration. This was observed for the first time by Nissl in 1892 (Tetzlaff et al., 1986). Chromatolysis starts in hours following nerve section and may evolve into either survival or apoptosis (Martin et al., 1999). Cell death occurs in up to 35% of dorsal root ganglia neurons and less so in motor neurons (McKay Hart et al., 2002; Zhang et al., 2004). In surviving neurons, cell nuclei migrate to the pole opposite the axonal hillock. The nuclei and nucleoli increase in volume probably due to an increase in synthesis and content of RNA (Tetzlaff et al., 1996). At ultrastructural level there is destruction of the granular endoplasmic reticulum and an increase in the number and size of neurofilaments that, usually, decrease progressively after 3 weeks (Tetzlaff et al., 1986). Transneuronal changes also take place because of synapse stripping. Degenerated synapses may be replaced by sprouts of neighbouring axons (Graeber et al., 1993). Axotomized motoneurons show a reduction in choline acetyltransferase (ChAT) and an increase of calcitonin gene-related peptide (CGRP) expression (Borke et al., 1993; Calderó et al., 1992). They also undergo plastic changes in their expression of ion channels, transducers, and receptors, and modify their neuronal electrical properties (Kuno et al., 1974; Titmus and Faber, 1990). Sympathetic neurons show a reduced expression of neuropeptide Y and tyrosine hydroxylase after axotomy, while they overexpress the vasoactive intestinal peptide (VIP), galanin, and substance P (Zigmond, 1997). Primary sensory neurons also change their phenotype with regard to messengers after peripheral injury. Particularly, substance P and CGRP are markedly downregulated in peptidergic small DRG neurons after axotomy, whereas other neuropeptides such as VIP, galanin, and neuropeptide Y are increased (McGregor et al., 1984; Villar et al., 1991; Wakisaka et al., 1991). There is some neurophysiological evidence for the enhanced neuronal excitability after nerve lesion. At onset of reinnervation, axons of the regenerating nerve may be hypoexcitable to the electrical stimulus. This will activate, instead, the neighbouring terminals from another nerve, causing an afferent input that may be

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sufficient to excite the hyperexcitable parent motoneuron and generate a reflex muscle action potential (Cossu et al., 1999). The fact that reflexly elicited muscle responses are obtained with much lower stimulus intensity than direct responses indicates that transsynaptic activation of the motoneuron is far easier than axonal depolarization and constitute indirect evidence for the presence of motoneuronal excitability enhancement. In regenerating nerves, electrophysiological studies of tracking threshold have shown a significant change in excitability (Moldovan and Krarup, 2004; Sawai et al., 2008), which may cause ectopic activity and abnormal responses to mechanical and thermal inputs (Gorodetskaya et al., 2003; Michaelis et al., 1999; Serra et al., 2010). Regenerating axons may be hypoexcitable to certain types of inputs and hyperexcitable to others. They may generate spontaneous (ectopic) activity in the site of the lesion and along the course of the unstable regenerating nerve. In the motor axons, ectopic discharges may cause myokymia, fasciculations, spasms or other type of visible activity that would be relatively easy to identify and document. However, similar activity in the sensory axons would give rise to abnormal sensory experiences, such as dysesthesia and pain, which cannot be reflected in objective recording systems. Neuropathic pain is one of the most distressing consequences of injuries in sensory axons, likely deriving from activity in regenerating sensory axons with unstable excitability. Ectopic discharges in unmyelinated fibres are actually a paradigmatic result of microneurography in patients with neuropathic pain (Serra et al., 2010). 2.4. Reinnervation activity in non-injured nerves The growth of axons from a parent neuron is known to occur after a focal lesion even in neurons that have not been damaged. Indeed, this is the basis for collateral reinnervation, a process that takes place when there is functional (transient or permanent) loss of motor units. Collateral sprouting is frequent in diseases affecting alpha motoneurons such as poliomyelitis or amyotrophic lateral sclerosis. In motoneuron diseases, the growth in size of the motor unit parallels the reduction in the number of active motor units (Sartucci et al., 2007). However, reinnervation also occurs in motor units belonging to nerves that have not been damaged. This has been shown with skin incision and excision lesions in humans (Rajan et al., 2003). A few weeks after skin incision, axons growing from neighbouring epidermal fibres penetrate the denervated segment, while those issued from lesioned dermal axons are delayed in their growth towards the epidermis. In a model of recurrent laryngeal nerve injury in rats, axotomy was followed by reinnervation activity in the non-damaged superior laryngeal nerve, innervating the same muscle fibres previously activated by the recurrent nerve (Hydman and Mattsson, 2008). In the same line, both, axotomized and intact neurons, can generate axonal-like extensions in a tissue medium in the laboratory (Agius and Cochard, 1998), although some differences in the properties of growing neurites have been reported. Experimental axotomy has beeen used to facilitate reinnervation after end-to-side neurorrhaphy in an animal experimentation model (Hayashi et al., 2008). In this procedure, the distal stump of a damaged nerve is connected to the side of a ‘donor’ nerve. However, for axonal growing to occur in the damaged nerve, the donor nerve itself has to be axotomized. A more common example of distant effects of nerve damage occurs with local injections of botulinum toxin, which cause distant reinnervation phenomena (Olney et al., 1988; Garner et al., 1993; Roche et al., 2008). Even thought the mechanisms accounting for such a phenomenon are not completely understood, one of the possibilities is that the transient loss of function stimulates a widespread reinnervation process. Recognition of the relationship between certain clinical conditions and plastic changes triggered by nerve lesions in intact

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nerves may not be an easy task. A far-reaching but plausible hypothesis would be the triggering by a peripheral nerve lesion of new synaptic activity (and even axonal growth) in the central nervous system, as one of the mechanisms of the so-called lesion-induced plasticity (Costa et al., 2006). 3. Clinical syndromes derived from abnormalities in the reinnervation process 3.1. Postparalytic facial syndrome Peripheral facial palsy (PFP) is a relatively well known example of reinnervation-related disorders in humans. While at onset it shows features of compensatory effects in the contralateral side of the face, later consequences of aberrant regeneration give rise to synkinesis and other signs of hyperactivity in the previously paralyzed side. In a few instances, the first complaint of patients with PFP is enhancement of the spontaneous blinking rate in the contralateral eye. Excess blinking may also be accompanied by clinically relevant hyperactivity in the spared hemiface that has led to a few reports on the possibility of a Bell’s palsy-induced contralateral blepharospasm (Chuke et al., 1996; Baker et al., 1997). These authors found that the blepharospasm-like sustained contraction of the facial muscles of the side contralateral to the paralysis was relieved by helping to close the eye with a weight added to the upper eyelid. Further evidence in the same direction was reported by Manca and coworkers (2001), who analyzed the size differences between the responses of the blink reflex recorded in the non-paralyzed side to ipsilateral (R2) and contralateral (R2c) supraorbital nerve electrical stimulation. These authors observed larger R2c than R2 responses in 80.9% of patients and in only 23.1% of control subjects (chi square = 13.3; p < 0.01). An example of such type of abnormal findings is shown in Fig. 1. The most likely explanation for those observations is that, after the facial nerve lesion, motoneurons express an enhanced excitability that make them react to more inputs than in healthy persons, as in a process of sensitization. Such enhancement involves not only the motoneurons of the damaged nerve but also those of the contralateral nerve. More changes occur in the contralateral facial nerve after unilateral facial palsy. It is relatively common to observe small polyphasic motor unit action potentials in the orbicularis oris of patients with unilateral peripheral facial palsy with complete denervation at 1–2 months after the lesion. It is impossible for the axons growing in the damaged nerve to have reached the muscle by that time and, therefore, these action potentials must be generated in another nerve. Trojaborg (1977) found reinnervation signs in the contralateral facial nerve and calculated a conduction

velocity of about 5 m/s across the oral commissure, suggesting that the axons were probably innervating muscle fibres that crossed the midline. A different view has been expressed by Gilhuis et al. (2001), who suggested that axons actually grow crossing the midline and innervating not only the orbicularis oris but other muscles as well. In a series of 25 patients, we have also found that contralateral reinnervation was limited to the orbicularis oris and the conduction velocity across the midline was compatible with muscle fibre propagation rather than with axonal function (Fig. 2). Hence, this is an example of regeneration triggered in a non-injured nerve by damage in the contralateral one. This might be due to a widespread induction of regenerative processes, triggered by chemical changes generated in the lesion site. However, in sphincter-like muscles such as the orbicularis oculi, denervation of circular muscle fibres may be a strong additional stimulus for the contralateral facial nerve to undergo axonal regeneration changes. After axonal damage of the facial nerve, abnormal regeneration is to be expected, given the usually rich branching of the nerve distal to the lesion site. Regenerating errors in a pure motor nerve such as the facial nerve might be of two types: first, the axon generated in a motoneuron previously activating one muscle ends up in a funiculus going to another muscle. Second, one axon going previously to a specific muscle branches into two or more axons going to different muscles that might have different functions. In the case of the facial nerve, regenerating axons might undergo reinnervation errors implying not only facial motor axons, but also involving parasympathetic axons of the intermediary nerve of Wrisberg. This nerve accompanies the facial nerve in the petrossal canal, and may be included in the lesion if this involves proximal sites. In these instances, parasympathetic axons may enter the facial nerve and reach motor end plates, as motor axons of the facial nerve may enter the parasympathetic funiculi and reach the lachrymal gland or the gustatory receptor. Lachrymation and hemifacial sweating when activating facial muscles is one of the consequences of such reinnervation errors. Perioral muscle reinnervation after complete facial palsy begins usually at about 3 months after onset of symptoms. Cossu et al. (1999) examined the characteristics of the reinnervation process when only a few polyphasic motor unit action potentials were present. These authors found signs of enhanced motoneuronal activity and of synkinesis from the very onset of reinnervation. Small motor unit action potentials were continuously firing with little voluntary control, some units fired time locked to spontaneous blinking and, in 4 out of 18 patients with synkinesis, a few units fired in bursts time locked to the inhalation phase of breathing, a finding also reported by Pavesi et al. (1994). The same motor unit action potentials were elicited by single electrical stimuli

Fig. 1. Recording of the blink reflex from the orbicularis oculi (OOc) in a healthy subject (A and C) and in a patient with left side peripheral facial palsy (B and D) 1 month after onset. Each graph shows two superimposed responses to show consistency of the observations. (A) and (B) show the responses recorded in the right side to right supraorbital nerve stimulation while (C) and (D) show the responses recorded in the right side to left supraorbital nerve stimulation. Note that the R2c is larger than the R2 in the patient (i.e., there is a larger size of the responses elicited by stimulation of the affected side than of the non-affected side), the contrary of what is seen in the healthy control.

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Fig. 2. Recording with needle electrode from the orbicularis oris to electrical stimuli applied to the ipsilateral (upper single trace) and contralateral facial nerve from tragus to oral commissure in steps of 2 cm approximately (five lower traces). Note the short segmental latency change in comparison to the relatively long distal latency, compatible with a rather long distal segment of muscle membrane action potential propagation.

delivered to the supraorbital and facial nerves of both sides, indicating the exaggerated responsiveness of reinnervating facial motoneurons in comparison to hypoexcitable regenerating axons. It seems likely that the electrical stimulus intended to activate the facial nerve at the tragus inevitably also activated cutaneous terminals of the 3rd branch of the trigeminal nerve, which reached the facial nucleus and were capable of triggering a reflex response. These abnormalities will eventually lead to the so-called postparalytic facial syndrome (Valls-Solé, 2007), featuring spontaneous motor unit activity, synkinesis and mass contractions. Such complex disturbance of voluntary and automatic activation of facial muscles may occasionally lead to severe emotional disturbances (VanSwearingen et al., 1999). A form of facial nerve dysfunction, essential hemifacial spasm (Auger, 1979), presents usually with no conduction block or denervation signs. In spite of that, some electrophysiological observations lead to think that there is a chronic lesion in the proximal part of the nerve. The most commonly referred to is ephapsis, the observation of activity in one facial muscle when the nerve branch innervating another muscle is stimulated (Nielsen, 1984a,b). Essential hemifacial spasm is attributed to irritation of the nerve by an aberrant vessel in the posterior fossa (Møller, 1999; Jankovic, 2009) and a debate is still not settled on whether the abnormal responses are generated at axonal level in the site of assumed irritation or at the nuclear level after some form of kindling (Møller, 1999). 3.2. Reinnervation-related laryngeal disorders The larynx is a complex organ, containing several small muscles supplied by one main nerve, the vagus. Laryngeal muscles display unique histochemical profiles (mixed non-predominant slow and fast fibres) and unique myosin heavy chain isoforms, with a high rate of hybrid fibres between and within muscles (Wu et al., 2000). This makes the laryngeal muscles strikingly different from limb muscles, which display predominantly one kind of fibre (either slow type I or fast type II). The recurrent laryngeal nerve innervates almost all vocal cord related muscles, notably those closing the larynx such as the thyroarytenoid muscle, and the only one that abducts the vocal cords, the posterior cricoarytenoid mus-

cle. The exception is the posterior cricothyroid muscle, which is innervated through the external laryngeal branch of the vagus. It has been estimated that about 75% of axons are involved in adduction while the remaining 25% are involved in abduction of the vocal cords (Crumley, 1989). Lesions of the laryngeal nerves may be due to many causes, including traumatisms, compressions and idiopathic neuritis. Aphonia or disphonia are the most apparent major consequences of complete or, more often, partial nerve lesions. After axonal lesions, laryngeal nerves regenerate and reinnervate the laryngeal muscles. However, as expected, some reinnervation errors might ensue because of the highly specific control necessary for the function of laryngeal muscles. Axotomy of the laryngeal nerves has been carried out in experimentation animals to study reinnervation (Woodson, 1993). It has also been done for the treatment of spasmodic dysphonia (Netterville et al., 1991). Woodson (2008) studied experimental reinnervation of the laryngeal muscles in cats, and reported that reinnervation was preferential to the thyroarytenoid muscle with respect to the posterior cricoarytenoid muscle. Thus, while paralyzed vocal cords due to completely severed nerves were lying in a lateral position in the larynx, reinnervation led to a different abnormal position of the vocal cord, which was more medial than in non-injured cats. This may indeed be better for closing the glottal space, but it is not necessarily beneficial for vocal cord function. In humans, paraclinical evaluation of the larynx is done nowadays mainly using flexible fibre optic laryngoscopy with videostroboscopy and needle or (better) hook type fine-wire electrodes electromyography (Hillel, 2001). While laryngoscopy allows for determining the position and movility of the vocal cords, electromyography may help in ascertaining the neurogenic origin of vocal cord paresis, for instance, after traumatisms during intubation for external ventilation in patients with loss of consciousness. Dysphonia may be due not only to the paralysis but also to the loss of muscle control after reinnervation (Woodson, 2008). Blitzer et al. (1996) reported that, even in immobile vocal cords there is often electromyography activity, indicating that the paralysis is not due to lack of muscle activity but, probably to lack of a correctly controlled muscle contraction. Mispositioning of vocal cords and abnormal control of their movement after nerve lesions may be due to reinnervation errors and synkinesis (Crumley, 1989;

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Paniello and West, 2000; Gordon and Boyd, 2003; Maronian et al., 2004). The resultant laryngeal dyscoordination can cause voice disorders and airway compromise (Woo and Mangaro, 2004). Demonstrating reinnervation errors and synkinesis is a rather difficult task in muscles that are almost continuously active and which resting state is little controlled by will, such as is the case in laryngeal muscles. Some authors have suggested classifying the synkinesis on the basis of laryngeal function: good or bad synkinesis depending on whether they help to mantain the position of the vocal fold or provoke spasms and complications (Crumley, 2000; Wani and Woodson, 1999). In those instances, synkinesis was diagnosed when a task known to activate a given muscle was accompanied by activity in another muscle not directly involved in the movement. For instance, vocalization (‘eeee’) requires activity in the thyroarytenoid muscle but not in the posterior cricoarytenoid muscle, while a sniff requires activity in the posterior cricoarytenoid muscle but not in the thyroarytenoid muscle. However, Hillel (2001) reported that, even if activity is not required, muscles of the larynx may co-contract in order to stabilize the vocal cords in a certain position. Therefore, Maronian et al. (2004) used a stringent criteria than Crumley (2000) to define synkinesis by requiring that activity in the posterior cricoarytenoid muscle during vocalization was of an amount equal or larger than that seen during a sniff. According to Maronian et al. (2004), the positive diagnosis of synkinesis should be only made in studies of awake and fully cooperative subjects using, if possible fine-wire electrodes, which pick up less activity as volume conduction from neighbour muscles. Reinnervation might be faster and easier for some muscles than for others. In the larynx, the thyroarytenoid muscle seems to receive a larger number of axons than the posterior cricoarytenoid muscle. However, this may be just apparent due to the fact that there is a larger amount of axons and muscle fibres in the adductor than in the abductor muscles or to the fact that the axons going to the posterior cricoarytenoid muscle have a longer distance to run than those going to the thyroarytenoid muscle. It is possible, though, that there are intrinsic muscle differences in the response to reinnervation, either in the form of production of local growth and chemotactic factors or in the form of fibre characteristics that allow them to be innervated more or less easily (Wang et al., 2002). 3.3. Abnormal hand and finger movements after ulnar nerve lesions The ulnar nerve has peculiar anatomo-functional characteristics. It innervates the majority of intrinsic hand muscles, a very important group of muscles for skilfull human activities. Ulnar nerve lesions are relatively common. They occur most frequently at the elbow but may also take place at the wrist or in other points along the course of the nerve. Ulnar nerve compression lesions may not cause more meaningful clinical problems than other focal nerve lesions. However, ulnar nerve reinnervation errors after axonal degeneration are likely to cause a severe handicap in the subject’s manual ability (Dell and Sforzo, 2005). The small ulnarinnervated hand muscles are usually activated following specific patterns of reciprocal contraction in various degrees for performance of delicate manual actions. This is the case, for instance, with writing, playing an instrument or a few other skilfull human activities. Such learned, highly complex and specificity-demanding motor programs require a very careful control of the degree of reciprocal muscle activation and relaxation. Perfect execution of those motor programs is necessary for the subject’s success in his or her performance. The ability to learn those motor programs is likely not the same for all subjects. However, subjects with the same capacity may also face different success in their performance depending on the state of their peripheral machinery. Musculoskeletal disorders would easily interfere with the subject’s perfor-

mance (Leijnse and Hallett, 2007; Rosset-Llobet et al., 2009). Repetitive movements have been shown to induce simultaneous changes in peripheral and central nervous system (Coq et al., 2009). In the same way, nerve lesions implying reinnervation errors should be considered as a cause of disordered motor control in some patients. As with the vocal cord synkinesis, the electrophysiological methods nowadays available for recognizing ulnar nerve reinnervation errors may not give sufficient information for the positive assessment of such dysfunction in many cases. In compression syndromes, nerve conduction studies may show conduction block or segmental demyelination. If an axonal lesion occurs, needle electromyography can show denervation potentials in the hand and forearm muscles innervated by the ulnar nerve. In lesions located at a site proximal to branching points for the intrinsic hand muscles, misdirected regrowth of motor axons will lead to connections to wrongly targetted muscle fibres. Hand muscles innervated by the ulnar nerve have different properties (Bae et al., 2009), making it possible for growing axons to be more attracted by certain muscle fibres than by others. Chronic irritative damage has been described for the ulnar nerve at points where it is vulnerable. Satya-Murti and Layzer (1976), and later Loron et al. (1985), suggested a parallelism between the dimpling observed in some patients in the hypothenar muscles and the hemifacial spasm. Unfortunately, there is very little evidence for the degree of specificity in muscle fibre innervation by a given motorneuron. As in laryngeal muscles, excessive unwanted co-contraction might be a significant problem but it is difficult to judge when co-contraction is inappropriate. However, a very clear approach to the diagnosis of aberrant reinnervation is possible in mixed nerves such as the ulnar nerve. In these nerves, the possibility exists that motor axons follow an endoneurial tube leading to a sensory terminal. Electrophysiological evidence for the reinnervation errors may be obtained by the elicitation of muscle action potentials to electrical stimulation of cutaneous nerves at a latency that is incompatible with a reflex course involving the spinal cord (Montserrat and Benito, 1990). In our department, we have prospectively and systematically examined 21 traumatic ulnar nerve injured patients for the possibility of generation of abnormal muscle action potentials recorded with a needle electrode from the adductor digiti minimi by stimulating the digital nerves of the 5th finger, at various times after the lesion. During reinnervation, usually between 3 and 6 months after the lesion, we were able to record two types of responses (Fig. 3). The first response, of relatively early latency, appeared very steadily and consistently to successive stimuli at the same latency, with almost no jitter. The second response, of longer latency, appeared less constantly and had a noticeable jitter and some variation in its shape. The second response could be occasionally elicited also by stimuli applied to other cutaneous nerves of the same limb, i.e., the 3rd finger. The latency of the first response reduced progressively in successive exams. Therefore, we believe that the early response is due to an abnormal sensorimotor axonal reflex, which latency shortens because of progressive myelination of the growing axons. The second response, which jitter suggests a transynaptic event, is likely the consequence of an enhanced ulnar motoneuronal hyperexcitability: as in the case of peripheral facial palsy, reinnervating ulnar nerve motoneurons could fire at the arrival of sensory excitatory inputs from various sources due to the decreased inhibitory control. While the axon reflex is usually of small size and, probably, is not likely to cause by itself any functional disturbance, it shows rather clearly that an abnormal reinnervation has taken place, and brings about a pathophysiological explanation for some motor dysfunctions. The response originated as a result of enhanced motoneuronal excitability has probably a clearer functional

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Fig. 3. Muscle action potentials elicited in the adductor digiti minimi muscle by electrical stimulation of the digital nerves of the 5th finger in a representative patient who suffered a complete traumatic section of the ulnar nerve at the distal 1/3 of the forearm. Recordings in A were taken at about 4 months (upper trace) and 5 months (lower trace) after injury. See the ephaptic response at a latency of about 60 ms in the upper trace and 55 ms in the lower trace. Recordings in B were taken from another patient with also a complete ulnar nerve section at mid forearm 6 months previously. Observe two types of response: the early action potential (arrowheads), which is stable in latency and morphology as a likely consequence of ephaptic sensorimotor connection, and the late action potential, which has more marked jitter and changes in shape, likely generated transynaptically due to motoneuronal hyperactivity.

correlate. Hyperactivity can be seen in denervated muscles. Spontaneous, involuntary and often unperceived tiny movements of the toes or fingers may occur as a result of the combined deafferentation and motoneuronal hyperactivity in patients with peripheral nerve injuries. Furthermore, these movements are non-natural, as they are mediated by abnormal reinnervation. Typical abnormal finger postures seen in our patients are: involuntary repetitive flexion of the proximal methacarpo-phalangeal joint of the 3rd or 4th fingers, likely due to the action of the 3rd and 4th lumbrical muscles; a tonic slight adduction deviation of the 3rd finger, and an exaggerated flexion of the 5th finger (Fig. 4). Abnormalities in performing skilfull actions are a logic consequence of motor control disturbances. This condition is sometimes referred as peripheral dystonia or pseudodystonia (Schott, 1985). It has been described in patients with causalgia or complex regional pain syndrome types I or II (Scherokman et al., 1986; Scaioli et al., 1996; Charness et al., 1996; Frucht et al., 2000). It is possible that patients who have some genetic predisposition develop dystonic postures after nerve damage (Bhatia et al., 1993; Bohlhalter et al., 2007). However, it seems a perfectly reasonable hypothesis that abnormal posturing due to peripheral nerve lesions causes a plastic change in the central nervous system in an attempt to compensate for the erroneous outcome. Aberrant axonal innervation and ephaptic transmission are likely less amenable than the central nervous system to plastic changes since they would imply modifying again the peripheral nerve connections.

scribed by Ross in 1958, is usually known as compensatory hyperhidrosis (CH). There are two main peripheral neuropathic defects that have been associated with CH: iatrogenic sympathectomy and distal polyneuropathies. It may also occur, though, in focal neuropathic lesions such as in gustatory sweating resulting from damage to the auriculotemporal nerve with aberrant innervation of normal sympathetically innervated facial sweat glands by parasympathetic nerve fibres through the chorda tympani (Saito, 1999). The eponym Frey’s syndrome is nowadays used to describe gustatory sweating and facial palsy occuring often after parotidectomy (Guntinas-Lichius et al., 2006). Similarly, a focal lesion of the sympathetic pathways is thought to be the cause of the Harlequin syndrome (Lance et al., 1988), consisting on unilateral erythema and hyperhidrosis together with contralateral anhidrosis (Fig. 5). Surgical sympathectomy is an effective therapeutic procedure for palmoplantar hyperhidrosis and facial blushing. The preferred surgical technique at present is thoracoscopic sympathectomy of the 2nd or 3rd sympathetic ganglion. This has an outstanding

3.4. Compensatory hyperhidrosis Hyperhidrosis is a common pathological condition of excessive secretion of the eccrine sweat glands in response to heat or emotional stimuli beyond physiologic need (Haider and Solish, 2005). It causes a significant negative impact on quality of life as well as impairments in social, physical, leisure, and occupational activities. Based on its etiology, hyperhidrosis can be primary (idiopathic) or secondary to a variety of medical disorders, such as infections and endocrine diseases (Shargall et al., 2008). A particular form of secondary hyperhidrosis is the one that develops in the context of a peripheral neuropathy involving parts of the body not affected anatomically by the denervation process. This condition, first de-

Fig. 4. Typical posture after ulnar nerve lesion.

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sive sweating in response to stimuli leading to emotional reactions (Bickel et al., 2004). This may trigger a compensatory reaction in axial zones, where the damage is less important. In polyneuropathies, sweat gland denervation hypersensitivity may also account for a peripheral cause of hyperhidrosis (Low et al., 1983). A form of CH may occur also in patients with Parkinson’s disease because the sudomotor skin response recorded from the palms was smaller in patients with hyperhidrosis than in patients with no sweating disturbances (Schestatsky et al., 2006). 4. Conclusion

Fig. 5. Uncontrolled sweating of the right lower limb in a patient with harlequin syndrome of unknown origin. Note the differences between the left side (dry) and the right side (wet) of the lady’s trousers.

success rate (Haider and Solish, 2005; Baumgartner et al., 2009), which is only diminished by the presence of CH as a secondary effect (Shuster, 1998; Chwajol et al., 2009). The reported incidence of mild to severe post-sympathectomy CH, usually involving the trunk, pelvic area and thighs, ranges from 35% to 98%. It has been recognized as more frequent and disturbing with more rostral denervation (Miller et al., 2009) and with more extensive gangliectomy (Weksler et al., 2009). Older age and a relatively large body mass index are also risk factors for the potential development of CH. Several studies suggest that post-sympathectomy CH may not be just due to a purely thermoregulatory compensation for the loss of sweating but to a much more complex mechanism involving the hypothalamus (Kopelman et al., 2000). Sweating is under regulation by neurons in the medial preoptic/anterior hypothalamic area (the primary thermosensitive area of the CNS). These neurons are spontaneously active, probably responding to inputs derived from their own oscillatory activity and from afferent thermoreceptive feedback (Benarroch, 2007). It has been shown that recovery of sympathetic activity by reinnervation improved CH significantly (Telaranta, 1998), which was attributed to restoration of afferent inflow to the hypothalamus. Therefore, CH is an examples of the close inter-relation between peripheral nerve lesions and central nervous system plastic changes. An indirect test to examine the function of the sympathetic circuit is the analysis of the sympathetic skin response (SSR). The SSR results from the synchronized activation of a number of sweat glands induced by a stimulus, usually an electrical shock (Vetrugno Liguori et al., 2003). Various authors have reported abnormalities of the SSR in patients with primary palmar hyperhidrosis (Chen et al., 1995; Lefaucheur et al., 1996; Manca et al., 2000) that persist after thoracic sympathectomy if responses are preserved (Lladó et al., 2005). Impaired sweating may be one of the first symptoms in patients with distal polyneuropathies (Stewart et al., 1992; Tugnoli et al., 1999). Axonal degeneration involving small fibres usually affects the sympathetic nerves, causing a reduced outflow to the sweat glands. In autonomic peripheral nerve involvement, such as in the hereditary sensory and autonomic neuropathies or in familial dysautonomia, lack of sweating in the extremities may be accompanied by excessive sweating in the trunk and head. The skin of the hands and feet becomes dry and may sustain severe trophic abnormalities resulting from neuronal-axonal damage in the autonomic nervous system fibres. In contrast, patients may complain of exces-

Dysfunctional outcome after a nerve lesion may derive from loss of motor and sensory fibres but, most often, it derives from errors in the reinnervation process, including inappropriate innervation of targets, axonal branching, axonal sprouting from unaffected nerves, hyperactivity in the parent neurons, and other less studied disorders. There are certainly many clinical conditions related to dysfunctions of reinnervation. Some of them may not be easily recognizable nor clearly documented by the available diagnostic means. Electrophysiological tests fall short in demonstrating some of the reinnervation abnormalities described here. In the same way that facial nerve lesions lead to hemifacial synkinesis, motor dysfunctions might be present in limb, neck or trunk muscles after a peripheral nerve lesion located rostral to relevant branching points. Abnormalities in motor control might cause abnormal postures and task-related dysfunctions that can mimic dystonia or tremor. In some instances, pain and motor dysfunction could appear in the same area. It is not unlikely that irritative lesions, frequently unnoticed in routine electrodiagnostic testing, trigger changes in the axons and the motoneurons that may be responsible for dystonic-like involuntary postures or movements in much the same way as it happens in the facial muscles in essential hemifacial spasm. References Agius E, Cochard P. Comparison of neurite outgrowth induced by intact and injured sciatic nerves: a confocal and functional analysis. J Neurosci 1998;18:328–38. Auger RG. Hemifacial spasm. Clinical and electrophysiologic observations. Neurology 1979;29:1261–72. Bae JS, Sawai S, Misawa S, Kanai K, Isose S, Kuwabara S. Differences in excitability properties of FDI and ADM motor axons. Muscle Nerve 2009;39:350–4. Baker RS, Sun WS, Hasan SA, Rouholiman BS, Chuke JC, Cowen DE, Porter JD. Maladaptive neural compensatory mechanisms in Bell’s palsy-induced blepharospasm. Neurology 1997;49:223–9. Baumgartner FJ, Bertin S, Konecny J. Superiority of thoracoscopic sympathectomy over medical management for the palmoplantar subset of severe hyperhidrosis. Ann Vasc Surg 2009;23:1–7. Benarroch EE. Thermoregulation: recent concepts and remaining questions. Neurology 2007;69:1293–7. Bhatia KP, Bhatt MH, Marsden CD. The causalgia-dystonia syndrome. Brain 1993;116:843–51. Bickel A, Axelrod FB, Marthol H, Schmelz M, Hilz MJ. Sudomotor function in familial dysautonomia. J Neurol Neurosurg Psychiatry 2004;75:275–9. Blitzer A, Jahn AF, Keidar A. Semon’s law revisited: an electromyographic analysis of laryngeal synkinesis. Ann Otol Rhinol Laryngol 1996;105:764–9. Bohlhalter S, Leon-Sarmiento FE, Hallett M. Abnormality of motor cortex excitability in peripherally induced dystonia. Mov Disord 2007;22:1186–9. Borisov AB, Dedkov EI, Carlson BM. Interrelations of myogenic response, progressive atrophy of muscle fibers, and cell death in denervated skeletal muscle. Anat Rec 2001;264:203–18. Borke RC, Curtis M, Ginsberg C. Choline acetyltransferase and calcitonin gene related peptide immunoreactivity in motoneurons after different types of nerve injury. J Neurocytol 1993;22:141–53. Brushart TM, Gerber J, Kessens P, Chen YG, Royall RM. Contributions of pathway and neuron to preferential motor reinnervation. J Neurosci 1998;18:8674–81. Calderó J, Casanovas A, Sorribas A, Esquerda JE. Calcitonin gene-related peptide in rat spinal cord motoneurons: subcellular distribution and changes induced by axotomy. Neuroscience 1992;48:449–61. Charness ME, Ross MH, Shefner JM. Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: clinical correlation in musicians. Muscle Nerve 1996;19:431–7.

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