Journal of the Peripheral Nervous System 18:331–335 (2013)
CASE REPORT
Is carpal tunnel decompression warranted for HNPP? Nicholas Earle and Douglas W. Zochodne Department of Clinical Neurosciences, University of Calgary, Calgary, Canada
Abstract
The role of carpal tunnel decompression surgery for patients that have hereditary neuropathy with liability to pressure palsy (HNPP) is currently unknown. Since recovery from carpal tunnel compression is often associated with remyelination or nodal reconstruction rather than axonal regeneration, it is uncertain whether the PMP22 deletion associated with HNPP interrupts myelin or nodal reconstitution. We describe two patients with genetically confirmed HNPP and symptomatic carpal tunnel syndrome that had clinical and electrophysiological improvement after surgical decompression. The findings indicate a capacity for conduction repair in HNPP. They also suggest a need for further investigation and discussion around whether to offer carpal tunnel decompression to symptomatic HNPP patients.
Key words: carpal tunnel syndrome, hereditary neuropathy with liability to pressure palsy, PMP22, remyelination, tomaculous neuropathy
Introduction
frequently in the second or third decade of life. The clinical course varies in severity, even within single families (Rizzuto et al ., 1993). Electrophysiological studies identify conduction slowing, block, or dispersion across entrapment sites that accompany more widespread and often asymptomatic abnormalities (Li et al ., 2002). The pathology includes focal myelin sheath thickening (sausage-like) referred to as ‘‘tomaculae’’, ‘‘onionbulb’’ formation and axonal degeneration (Madrid and Bradley , 1975 ; Saporta and Shy , 2013). Since the first report of HNPP in 1947 by de Jong, recently confirmed (Koehler and Baas, 2012), it is not clear if decompression surgery has a role in the treatment of this disease. Specifically, it is uncertain whether human nerve segments that harbor mutated myelin protein, PMP22 and altered myelin structural stability are capable of conduction repair, a process that may include remyelination, nodal reconstruction or both (Li et al ., 2013). Unfortunately, there is little guidance in the literature to direct clinicians whether to offer established and evidence based forms of decompression, such as carpal tunnel release to symptomatic HNPP patients. Here we describe two HNPP patients with clear clinical
Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease with recurrent sensory and motor nerve palsies usually precipitated by trivial trauma, stretch, or compression (Li et al ., 2004; Saporta et al ., 2011; Saporta and Shy , 2013). In the majority of cases (80%), HNPP is caused by deletion of the peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2. The remaining 20% have a variety of abnormalities including loss of function point mutations, small deletions, and insertions in the PMP22 gene (Mariman et al ., 1994; Li et al ., 2013). The product of this gene is a membrane glycoprotein that plays an important role in the formation and maintenance of compact myelin in the peripheral nervous system (Li et al ., 2013). Symptomatic patients usually present with sensory and motor deficits in the nerves liable to compression. The first symptoms occur more
Address correspondence to: Dr. Douglas W. Zochodne, 168 Heritage Medical Research Bldg, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Tel: +1 403-220-8759, Fax: +1 403-283-8731; E-mail: [email protected] © 2013 Peripheral Nerve Society
331
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Table 1. Baseline electrophysiological results.
Patient 1 Median motor Median sensory Ulnar motor Ulnar sensory Peroneal motor Sural sensory Patient 2 Median motor Median sensory Ulnar motor Ulnar sensory Normal
DML, SL R/L
CV R/L
CMAP (D, P) or SNAP R/L
7.8/7.2 NR/5.6 3.9/4.4 3.8/3.9 ND/9.1 ND/NR
41/44 NR/27 34, 43/33, 46 34/33 ND/35, 42 ND/NR
6.7, 6.6/6.2, 6.0 NR/10.7 7.8, 6.5, 6.0/6.6, 6.1, 5.2 13.8/11.4 ND/3.0, 2.7, 2.6 ND/NR
8.9/8.5 7.3/NR 3.6/ND 5.1/ND > 4.5 ms DML median, ulnar >6.2 ms DML peroneal
47/54 24/NR 61/ND 30/ND >49 m/s upper limbs >39 m/s lower limbs
5.2, 5.4/4.7, 4.2 4.0/NR 11.5, 10.6, 8.8/ND 9.0/ND >5.0 mV median, ulnar CMAPs >10.0 uV median, ulnar SNAPs >2.0 mV peroneal CMAP >6.0 uV sural SNAP
Note that ulnar and peroneal motor CMAPs were recorded from stimulation at three sites (ulnar-wrist, below and above elbow; peroneal-ankle, fibular head, knee). CMAP, amplitude of compound muscle action potential (distal, proximal); CV, conduction velocity; D, distal stimulation site; DML, distal motor latency; L, left side; ND, not done; NR, not recordable; P, proximal stimulation site; R, right side; SL, sensory latency; SNAP, amplitude of sensory nerve action potential.
and electrophysiological recovery following carpal tunnel decompression indicating a capacity to repair conduction and recover.
and 2) prompted a decision for decompression. Open decompression was associated with gradual clinical recovery, disappearance of pain and improvement in function and pinprick sensation in the right median distribution. Follow-up electrophysiology over the next 8 months confirmed recovery of both motor and sensory conduction across the carpal tunnel, with significant improvement in the median distal motor latency (Figs. 1 and 2). Antidromic sensory nerve action potentials (SNAPs) recorded over the index finger underwent a progressive delay and decline in amplitude preoperatively, disappearing during two studies over one year prior to the decompression then reappearing and rising in amplitude afterward. Over the same period of time, there were no changes in contralateral median or ipsilateral ulnar studies.
Patient 1 A 51-year-old right handed female presented with a history of neurological symptoms that began in her teens with numbness and tingling in her feet from wearing tight shoes. When she was 28, she developed a left ulnar neuropathy after painting and later had left scapular winging from wearing a heavy bag over her shoulder. By age 40 she developed mild progressive weakness with numbness and tingling of both hands that worsened despite use of a wrist splint. She worked as a librarian, was previously well and had no definite family history of neuropathy. Her findings included mild weakness of median and ulnar intrinsic hand muscles, worse on the right with mild wasting of the right thenar eminence. There was a reduction in light touch and pinprick sensation in the right median distribution sparing the palm and in the right and left ulnar distribution. Tinel’s sign was negative. There was distal loss of vibratory perception in the feet. The remaining neurological examination was normal. DNA dosage analysis at 17p11.2-12 confirmed a deletion diagnostic of HNPP. Electrophysiological studies identified bilateral moderate to severe median neuropathies at the wrist and moderate bilateral ulnar neuropathies at the elbow (Table 1). She was followed conservatively but progressive symptomatic changes in the right median nerve territory (Figs. 1
Patient 2 A 33-year-old right handed male presented to the Neurophysiology Laboratory 6 months after he fell from a fence hitting his head. He developed neck pain with right proximal shoulder girdle and upper extremity weakness. He had a winged scapula with deltoid and spinatus wasting and weakness, diffuse loss of reflexes and a small area of sensory loss over the right shoulder. A C5 radiculopathy was documented by needle electromyography. In addition, however, he had widespread abnormalities of nerve conduction prominent at sites of entrapment (Table 1). Further history provided a 10-year history of ‘‘asleep’’ sensations in his right hand without 332
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
cervical intraspinal space noted spinal stenosis secondary to osteophytes and disc bulging at C67 with spinal cord flattening and bilateral foraminal stenosis at the same level. He underwent an anterior C67 discectomy and fusion. The procedure was complicated by a right laryngeal nerve palsy but this gradually recovered without additional intervention.
Discussion Current management for HNPP focuses on the prevention of compression or stretch damage to peripheral nerves from prolonged activities and postures. Wrist splints and elbow pads help to protect the median and ulnar nerves from neurapraxic injury. The variability in the presentation and severity of HNPP makes it difficult to evaluate treatment. Presentations include recurrent positional short-term sensory symptoms, progressive mononeuropathy, generalized polyneuropathy sometimes resembling chronic inflammatory demyelinating polyneuropathy, chronic sensory neuropathy, and recurrent subacute polyneuropathy. Some patients are asymptomatic. In classic forms, recovery from episodes is complete at first but later may be only associated with partial recovery. Despite this variation in presentation, there is no evidence for a progressive myelin disorder associated with HNPP (Li et al ., 2002). Both of our patients had characteristic clinical, electrophysiological, and molecular features of HNPP (Andersson et al ., 2000 ; Koehler , 2003). The findings from our patients are important to consider for several reasons. In patient 1, her symptoms and electrophysiology clearly indicated slowly progressive compression of the median nerve with probable local demyelination across the wrist. Treatment was delayed until her symptoms were significantly disabling. Over the 10-year period since the original diagnosis, the distal motor latencies in three upper limb nerves increased, consistent with the natural history of HNPP. The increase, however, was much more prominent in the median territories. In the unoperated contralateral median territory, the prolonged distal motor latency persisted, whereas the decompressed nerve had a substantial recovery, to within the upper limit of the normal range. This was associated with gradual clinical improvement. In patient 2, there were two important messages. The first message, as above, was that his decompressed median nerve also underwent conduction repair with both electrophysiological and clinical recovery. The second issue was that cervical nerve roots may be targeted by this genetic abnormality rendering susceptibility to local compression. In addition, HNPP likely contributed to the laryngeal palsy, a
Figure 1. Serial supramaximal median nerve SNAPs (left) and CMAPs (right) from wrist stimulation prior (preop) and following carpal tunnel decompression in patient 1. Comparative traces from a normal subject are shown below. Note that the SNAP recorded over the index finger reappears on the postoperative study. The CMAP undergoes a significant improvement in its distal motor latency that is retained in studies over 18 months of follow-up. CMAP, amplitude of compound muscle action potential; SNAP, amplitude of sensory nerve action potential.
persistent numbness or weakness. In his teens he had a prior right foot drop and numbness in the peroneal distribution after playing hockey. This took 6 months to recover and left residual numbness on the dorsum of the foot. His mother had been diagnosed with carpal tunnel syndrome and a brother had upper limb symptoms suggestive of the same diagnosis. DNA dosage analysis at the 17p11.212 region indicated a deletion diagnostic of HNPP. At 4 months of follow-up his arm motor function had largely recovered. A year later he had mild symptoms in the left ulnar territory that resolved, then remained largely stable over the next few years. At 6 years following the diagnosis, he returned with a 5-month history of numbness, tingling, and pain involving the right hand. Unlike previous visits, sensory examination identified loss in the median territory. He was referred for carpal tunnel decompression and noticed improvement after the procedure. As in patient 1, the median nerve distal motor latencies significantly improved in the decompressed arm, but did not change in the contralateral median territory or ipsilateral ulnar territory (Fig. 2). His index median SNAP disappeared on the right preoperatively, then reappeared postoperatively. Ten years after his diagnosis he noted persistent pain in the right shoulder without a new neurological deficit. Magnetic resonance imaging (MRI) of the 333
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Figure 2. Serial median distal motor latencies (DML) in patients 1 and 2 recorded preoperatively (green arrow indicates last study prior to decompression) and postoperatively. In the top tracings, the ipsi (ipsilateral) studies (red) indicate the side on which decompression was carried out. Note the dramatic decline in the DML following decompression, in comparison to persistent prolongation in the contralateral median motor territory and an unchanged ipsilateral ulnar DML. In the lower traces, serial changes in the ipsilateral median amplitude of compound muscle action potential (CMAP), amplitude of sensory nerve action potential (SNAP) index finger amplitude, and sensory conduction velocity to the index finger are included. Note that the SNAPs disappeared preoperatively and reappeared postoperatively. No consistent change in CMAP amplitudes was identified.
represents either dispersion and disappearance below background signal, or sensory axon conduction block with resolution. Our patients provide persuasive evidence that carpal tunnel decompression can be offered to patients who have appropriate, persistent, and significant symptoms in the median territory. A single patient described by Taggart and Allen suggested a clinical benefit in ulnar neuropathy after decompression (Taggart and Allen, 2001). Despite this previous report and findings presented here, a rigorous clinical trial format is required to substantiate these ideas and to learn more about when intervention should be considered. It is also important to point out a number of caveats around our suggestions. Many patients do not have symptoms that accompany electrophysiological evidence of entrapment in the median or ulnar territories. In the absence of symptoms, the utility of decompression is unknown and cannot be recommended at this time. There is little rationale for decompressing more than one nerve
complication that arises because retraction of his anterior neck muscles is required during the procedure. The operative bed was not at the anatomical site of the nerve and would have been subject to stretch or compression, not direct surgical trauma, consistent with his course (Li et al ., 2004). The possibility of this complication was anticipated and discussed with the patient preoperatively. Our findings provide interesting neurobiological evidence that demyelinated human nerves with a mutation in PMP22 are capable of conduction repair, a process that may involve new remyelination or nodal reconstruction in both motor and sensory fibers. This has always been suspected in HNPP given the spontaneous improvement many patients experience. The findings reinforce the concept that abnormalities of mature myelin stability, rather than formation, account for the accumulation of deficits over time in HNPP patients. The progressive delay, then disappearance and reappearance of SNAPs is also interesting, indicating that loss of the SNAP amplitude 334
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Koehler PJ, Baas F (2012). Hereditary neuropathy with liability to pressure palsies. Diagnosis in the first family (1947) confirmed. J Peripher Nerv Syst 17:412–413. Li J, Krajewski K, Shy ME, Lewis RA (2002). Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name. Neurology 58:1769–1773. Li J, Krajewski K, Lewis RA, Shy ME (2004). Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies. Muscle Nerve 29:205–210. Li J, Parker B, Martyn C, Natarajan C, Guo J (2013). The PMP22 gene and its related diseases. Mol Neurobiol 47:673–698. Madrid R, Bradley WG (1975). The pathology of neuropathies with focal thickening of the myelin sheath (Tomaculous Neuropathy). J Neurol Sci 25:415–448. Mariman ECM, Gabreels-Festen AAWM, van Beersum SEC, Valentijn LJ, Baas F, Bolhuis PL, Jongen PJH, Ropers HH, Gabreels FJM (1994). Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies. Ann Neurol 36:650–655. Rizzuto N, Moretto G, Galiazzo RS (1993). Clinical spectrum of the tomaculous neuropathies. Report of 60 cases and review of the literature. Ital J Neurol Sci 14:609–617. Saporta MA, Shy ME (2013). Inherited peripheral neuropathies. Neurol Clin 31:597–619. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME (2011). Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 69:22–33. Taggart TF, Allen TR (2001). Surgical treatment of a tomaculous neuropathy. J R Coll Surg Edinb 46:240–241.
territory at one setting; only nerves with persistent symptoms should be considered. The evidence for decompression of ulnar nerves in non-HNPP patients, and the most appropriate technique to recommend is not fully established; in HNPP patients, we do not have suggestions about this territory. In our experience, many HNPP patients with ulnar neuropathy respond to conservative protection of the nerve over a period of 3–4 months. Similarly, we do not recommend multiple decompression procedures in an attempt to modify the natural history of HNPP.
Acknowledgements The authors acknowledge the input of Dr. William de Haas who performed carpal tunnel release in both patients. Dr. Steve Casha performed a cervical laminectomy on the second patient. The authors also acknowledge the assistance of staff members of the Neurophysiology Laboratory including Anita Thiessen, Shaohua Ge and Marilyn Keck.
References Andersson PB, Yuen E, Parko K, So YT (2000). Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology 54:40–44. Koehler PJ (2003). Hereditary neuropathy with liability to pressure palsies: the first publication (1947). Neurology 60:1211–1213.
335
CASE REPORT
Is carpal tunnel decompression warranted for HNPP? Nicholas Earle and Douglas W. Zochodne Department of Clinical Neurosciences, University of Calgary, Calgary, Canada
Abstract
The role of carpal tunnel decompression surgery for patients that have hereditary neuropathy with liability to pressure palsy (HNPP) is currently unknown. Since recovery from carpal tunnel compression is often associated with remyelination or nodal reconstruction rather than axonal regeneration, it is uncertain whether the PMP22 deletion associated with HNPP interrupts myelin or nodal reconstitution. We describe two patients with genetically confirmed HNPP and symptomatic carpal tunnel syndrome that had clinical and electrophysiological improvement after surgical decompression. The findings indicate a capacity for conduction repair in HNPP. They also suggest a need for further investigation and discussion around whether to offer carpal tunnel decompression to symptomatic HNPP patients.
Key words: carpal tunnel syndrome, hereditary neuropathy with liability to pressure palsy, PMP22, remyelination, tomaculous neuropathy
Introduction
frequently in the second or third decade of life. The clinical course varies in severity, even within single families (Rizzuto et al ., 1993). Electrophysiological studies identify conduction slowing, block, or dispersion across entrapment sites that accompany more widespread and often asymptomatic abnormalities (Li et al ., 2002). The pathology includes focal myelin sheath thickening (sausage-like) referred to as ‘‘tomaculae’’, ‘‘onionbulb’’ formation and axonal degeneration (Madrid and Bradley , 1975 ; Saporta and Shy , 2013). Since the first report of HNPP in 1947 by de Jong, recently confirmed (Koehler and Baas, 2012), it is not clear if decompression surgery has a role in the treatment of this disease. Specifically, it is uncertain whether human nerve segments that harbor mutated myelin protein, PMP22 and altered myelin structural stability are capable of conduction repair, a process that may include remyelination, nodal reconstruction or both (Li et al ., 2013). Unfortunately, there is little guidance in the literature to direct clinicians whether to offer established and evidence based forms of decompression, such as carpal tunnel release to symptomatic HNPP patients. Here we describe two HNPP patients with clear clinical
Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease with recurrent sensory and motor nerve palsies usually precipitated by trivial trauma, stretch, or compression (Li et al ., 2004; Saporta et al ., 2011; Saporta and Shy , 2013). In the majority of cases (80%), HNPP is caused by deletion of the peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2. The remaining 20% have a variety of abnormalities including loss of function point mutations, small deletions, and insertions in the PMP22 gene (Mariman et al ., 1994; Li et al ., 2013). The product of this gene is a membrane glycoprotein that plays an important role in the formation and maintenance of compact myelin in the peripheral nervous system (Li et al ., 2013). Symptomatic patients usually present with sensory and motor deficits in the nerves liable to compression. The first symptoms occur more
Address correspondence to: Dr. Douglas W. Zochodne, 168 Heritage Medical Research Bldg, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Tel: +1 403-220-8759, Fax: +1 403-283-8731; E-mail: [email protected] © 2013 Peripheral Nerve Society
331
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Table 1. Baseline electrophysiological results.
Patient 1 Median motor Median sensory Ulnar motor Ulnar sensory Peroneal motor Sural sensory Patient 2 Median motor Median sensory Ulnar motor Ulnar sensory Normal
DML, SL R/L
CV R/L
CMAP (D, P) or SNAP R/L
7.8/7.2 NR/5.6 3.9/4.4 3.8/3.9 ND/9.1 ND/NR
41/44 NR/27 34, 43/33, 46 34/33 ND/35, 42 ND/NR
6.7, 6.6/6.2, 6.0 NR/10.7 7.8, 6.5, 6.0/6.6, 6.1, 5.2 13.8/11.4 ND/3.0, 2.7, 2.6 ND/NR
8.9/8.5 7.3/NR 3.6/ND 5.1/ND > 4.5 ms DML median, ulnar >6.2 ms DML peroneal
47/54 24/NR 61/ND 30/ND >49 m/s upper limbs >39 m/s lower limbs
5.2, 5.4/4.7, 4.2 4.0/NR 11.5, 10.6, 8.8/ND 9.0/ND >5.0 mV median, ulnar CMAPs >10.0 uV median, ulnar SNAPs >2.0 mV peroneal CMAP >6.0 uV sural SNAP
Note that ulnar and peroneal motor CMAPs were recorded from stimulation at three sites (ulnar-wrist, below and above elbow; peroneal-ankle, fibular head, knee). CMAP, amplitude of compound muscle action potential (distal, proximal); CV, conduction velocity; D, distal stimulation site; DML, distal motor latency; L, left side; ND, not done; NR, not recordable; P, proximal stimulation site; R, right side; SL, sensory latency; SNAP, amplitude of sensory nerve action potential.
and electrophysiological recovery following carpal tunnel decompression indicating a capacity to repair conduction and recover.
and 2) prompted a decision for decompression. Open decompression was associated with gradual clinical recovery, disappearance of pain and improvement in function and pinprick sensation in the right median distribution. Follow-up electrophysiology over the next 8 months confirmed recovery of both motor and sensory conduction across the carpal tunnel, with significant improvement in the median distal motor latency (Figs. 1 and 2). Antidromic sensory nerve action potentials (SNAPs) recorded over the index finger underwent a progressive delay and decline in amplitude preoperatively, disappearing during two studies over one year prior to the decompression then reappearing and rising in amplitude afterward. Over the same period of time, there were no changes in contralateral median or ipsilateral ulnar studies.
Patient 1 A 51-year-old right handed female presented with a history of neurological symptoms that began in her teens with numbness and tingling in her feet from wearing tight shoes. When she was 28, she developed a left ulnar neuropathy after painting and later had left scapular winging from wearing a heavy bag over her shoulder. By age 40 she developed mild progressive weakness with numbness and tingling of both hands that worsened despite use of a wrist splint. She worked as a librarian, was previously well and had no definite family history of neuropathy. Her findings included mild weakness of median and ulnar intrinsic hand muscles, worse on the right with mild wasting of the right thenar eminence. There was a reduction in light touch and pinprick sensation in the right median distribution sparing the palm and in the right and left ulnar distribution. Tinel’s sign was negative. There was distal loss of vibratory perception in the feet. The remaining neurological examination was normal. DNA dosage analysis at 17p11.2-12 confirmed a deletion diagnostic of HNPP. Electrophysiological studies identified bilateral moderate to severe median neuropathies at the wrist and moderate bilateral ulnar neuropathies at the elbow (Table 1). She was followed conservatively but progressive symptomatic changes in the right median nerve territory (Figs. 1
Patient 2 A 33-year-old right handed male presented to the Neurophysiology Laboratory 6 months after he fell from a fence hitting his head. He developed neck pain with right proximal shoulder girdle and upper extremity weakness. He had a winged scapula with deltoid and spinatus wasting and weakness, diffuse loss of reflexes and a small area of sensory loss over the right shoulder. A C5 radiculopathy was documented by needle electromyography. In addition, however, he had widespread abnormalities of nerve conduction prominent at sites of entrapment (Table 1). Further history provided a 10-year history of ‘‘asleep’’ sensations in his right hand without 332
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
cervical intraspinal space noted spinal stenosis secondary to osteophytes and disc bulging at C67 with spinal cord flattening and bilateral foraminal stenosis at the same level. He underwent an anterior C67 discectomy and fusion. The procedure was complicated by a right laryngeal nerve palsy but this gradually recovered without additional intervention.
Discussion Current management for HNPP focuses on the prevention of compression or stretch damage to peripheral nerves from prolonged activities and postures. Wrist splints and elbow pads help to protect the median and ulnar nerves from neurapraxic injury. The variability in the presentation and severity of HNPP makes it difficult to evaluate treatment. Presentations include recurrent positional short-term sensory symptoms, progressive mononeuropathy, generalized polyneuropathy sometimes resembling chronic inflammatory demyelinating polyneuropathy, chronic sensory neuropathy, and recurrent subacute polyneuropathy. Some patients are asymptomatic. In classic forms, recovery from episodes is complete at first but later may be only associated with partial recovery. Despite this variation in presentation, there is no evidence for a progressive myelin disorder associated with HNPP (Li et al ., 2002). Both of our patients had characteristic clinical, electrophysiological, and molecular features of HNPP (Andersson et al ., 2000 ; Koehler , 2003). The findings from our patients are important to consider for several reasons. In patient 1, her symptoms and electrophysiology clearly indicated slowly progressive compression of the median nerve with probable local demyelination across the wrist. Treatment was delayed until her symptoms were significantly disabling. Over the 10-year period since the original diagnosis, the distal motor latencies in three upper limb nerves increased, consistent with the natural history of HNPP. The increase, however, was much more prominent in the median territories. In the unoperated contralateral median territory, the prolonged distal motor latency persisted, whereas the decompressed nerve had a substantial recovery, to within the upper limit of the normal range. This was associated with gradual clinical improvement. In patient 2, there were two important messages. The first message, as above, was that his decompressed median nerve also underwent conduction repair with both electrophysiological and clinical recovery. The second issue was that cervical nerve roots may be targeted by this genetic abnormality rendering susceptibility to local compression. In addition, HNPP likely contributed to the laryngeal palsy, a
Figure 1. Serial supramaximal median nerve SNAPs (left) and CMAPs (right) from wrist stimulation prior (preop) and following carpal tunnel decompression in patient 1. Comparative traces from a normal subject are shown below. Note that the SNAP recorded over the index finger reappears on the postoperative study. The CMAP undergoes a significant improvement in its distal motor latency that is retained in studies over 18 months of follow-up. CMAP, amplitude of compound muscle action potential; SNAP, amplitude of sensory nerve action potential.
persistent numbness or weakness. In his teens he had a prior right foot drop and numbness in the peroneal distribution after playing hockey. This took 6 months to recover and left residual numbness on the dorsum of the foot. His mother had been diagnosed with carpal tunnel syndrome and a brother had upper limb symptoms suggestive of the same diagnosis. DNA dosage analysis at the 17p11.212 region indicated a deletion diagnostic of HNPP. At 4 months of follow-up his arm motor function had largely recovered. A year later he had mild symptoms in the left ulnar territory that resolved, then remained largely stable over the next few years. At 6 years following the diagnosis, he returned with a 5-month history of numbness, tingling, and pain involving the right hand. Unlike previous visits, sensory examination identified loss in the median territory. He was referred for carpal tunnel decompression and noticed improvement after the procedure. As in patient 1, the median nerve distal motor latencies significantly improved in the decompressed arm, but did not change in the contralateral median territory or ipsilateral ulnar territory (Fig. 2). His index median SNAP disappeared on the right preoperatively, then reappeared postoperatively. Ten years after his diagnosis he noted persistent pain in the right shoulder without a new neurological deficit. Magnetic resonance imaging (MRI) of the 333
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Figure 2. Serial median distal motor latencies (DML) in patients 1 and 2 recorded preoperatively (green arrow indicates last study prior to decompression) and postoperatively. In the top tracings, the ipsi (ipsilateral) studies (red) indicate the side on which decompression was carried out. Note the dramatic decline in the DML following decompression, in comparison to persistent prolongation in the contralateral median motor territory and an unchanged ipsilateral ulnar DML. In the lower traces, serial changes in the ipsilateral median amplitude of compound muscle action potential (CMAP), amplitude of sensory nerve action potential (SNAP) index finger amplitude, and sensory conduction velocity to the index finger are included. Note that the SNAPs disappeared preoperatively and reappeared postoperatively. No consistent change in CMAP amplitudes was identified.
represents either dispersion and disappearance below background signal, or sensory axon conduction block with resolution. Our patients provide persuasive evidence that carpal tunnel decompression can be offered to patients who have appropriate, persistent, and significant symptoms in the median territory. A single patient described by Taggart and Allen suggested a clinical benefit in ulnar neuropathy after decompression (Taggart and Allen, 2001). Despite this previous report and findings presented here, a rigorous clinical trial format is required to substantiate these ideas and to learn more about when intervention should be considered. It is also important to point out a number of caveats around our suggestions. Many patients do not have symptoms that accompany electrophysiological evidence of entrapment in the median or ulnar territories. In the absence of symptoms, the utility of decompression is unknown and cannot be recommended at this time. There is little rationale for decompressing more than one nerve
complication that arises because retraction of his anterior neck muscles is required during the procedure. The operative bed was not at the anatomical site of the nerve and would have been subject to stretch or compression, not direct surgical trauma, consistent with his course (Li et al ., 2004). The possibility of this complication was anticipated and discussed with the patient preoperatively. Our findings provide interesting neurobiological evidence that demyelinated human nerves with a mutation in PMP22 are capable of conduction repair, a process that may involve new remyelination or nodal reconstruction in both motor and sensory fibers. This has always been suspected in HNPP given the spontaneous improvement many patients experience. The findings reinforce the concept that abnormalities of mature myelin stability, rather than formation, account for the accumulation of deficits over time in HNPP patients. The progressive delay, then disappearance and reappearance of SNAPs is also interesting, indicating that loss of the SNAP amplitude 334
Earle and Zochodne
Journal of the Peripheral Nervous System 18:331–335 (2013)
Koehler PJ, Baas F (2012). Hereditary neuropathy with liability to pressure palsies. Diagnosis in the first family (1947) confirmed. J Peripher Nerv Syst 17:412–413. Li J, Krajewski K, Shy ME, Lewis RA (2002). Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name. Neurology 58:1769–1773. Li J, Krajewski K, Lewis RA, Shy ME (2004). Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies. Muscle Nerve 29:205–210. Li J, Parker B, Martyn C, Natarajan C, Guo J (2013). The PMP22 gene and its related diseases. Mol Neurobiol 47:673–698. Madrid R, Bradley WG (1975). The pathology of neuropathies with focal thickening of the myelin sheath (Tomaculous Neuropathy). J Neurol Sci 25:415–448. Mariman ECM, Gabreels-Festen AAWM, van Beersum SEC, Valentijn LJ, Baas F, Bolhuis PL, Jongen PJH, Ropers HH, Gabreels FJM (1994). Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies. Ann Neurol 36:650–655. Rizzuto N, Moretto G, Galiazzo RS (1993). Clinical spectrum of the tomaculous neuropathies. Report of 60 cases and review of the literature. Ital J Neurol Sci 14:609–617. Saporta MA, Shy ME (2013). Inherited peripheral neuropathies. Neurol Clin 31:597–619. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME (2011). Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 69:22–33. Taggart TF, Allen TR (2001). Surgical treatment of a tomaculous neuropathy. J R Coll Surg Edinb 46:240–241.
territory at one setting; only nerves with persistent symptoms should be considered. The evidence for decompression of ulnar nerves in non-HNPP patients, and the most appropriate technique to recommend is not fully established; in HNPP patients, we do not have suggestions about this territory. In our experience, many HNPP patients with ulnar neuropathy respond to conservative protection of the nerve over a period of 3–4 months. Similarly, we do not recommend multiple decompression procedures in an attempt to modify the natural history of HNPP.
Acknowledgements The authors acknowledge the input of Dr. William de Haas who performed carpal tunnel release in both patients. Dr. Steve Casha performed a cervical laminectomy on the second patient. The authors also acknowledge the assistance of staff members of the Neurophysiology Laboratory including Anita Thiessen, Shaohua Ge and Marilyn Keck.
References Andersson PB, Yuen E, Parko K, So YT (2000). Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology 54:40–44. Koehler PJ (2003). Hereditary neuropathy with liability to pressure palsies: the first publication (1947). Neurology 60:1211–1213.
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