Multiple Sclerosis and Related Disorders (2014) 3, 107–109
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis Greg M. Thaeran, Dean M. Wingerchuk, Jonathan L. Carter Department of Neurology, Mayo Clinic, Scottsdale, Arizona Received 23 January 2013; received in revised form 11 May 2013; accepted 19 May 2013
KEYWORDS Multiple sclerosis; Dalfampridine; Sensation disorders; Seizures; Trigeminal neuralgia; Paroxysmal neurologic symptoms
1.
Abstract Objective: Review cases of positive neurologic phenomena initiated or worsened with dalfampridine in patients with multiple sclerosis.
Background: Oral, extended release dalfampridine (4-aminopyridine or 4-AP) is a potassiumchannel blocker approved for the treatment of gait impairment in multiple sclerosis (MS). The enhanced conduction along demyelinated axons promoted by dalfampridine could potentially lead to development of positive neurologic phenomena. Methods: We reviewed the medical records of patients who were started on dalfampridine for activation of positive sensory or motor symptoms. Results: Four of 76 patients (5.3%) developed positive sensory symptoms within one month of starting dalfampridine; one additional patient had new-onset seizure. Cessation of dalfampridine was insufficient to resolve symptoms in two patients with recurrent trigeminal neuralgia. Conclusions: Initiation of dalfampridine may be associated with initiation or recurrence of positive sensory symptoms in patients with multiple sclerosis. The increased axonal conduction from potassium channel blockade may contribute to this exacerbation of positive sensory phenomena. & 2013 Elsevier B.V. All rights reserved.
Background
Oral extended-release dalfampridine, also known as 4aminopyridine or 4-AP, is a blocker of voltage-gated potassium channels. This medication has shown efficacy in treating gait impairment related to multiple sclerosis (MS) Goodman et al., 2009. Dalfampridine acts to enhance electrical conduction across demyelinated segments of axons affected by MS. The most serious potential adverse reaction is an increased risk for seizures, which is likely related to blockade n
Corresponding author. Tel.: +1 480 301 8100 E-mail address: [email protected] (G.M. Thaera).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.05.003
of potassium channels. Additional side effects include an increased incidence of urinary tract infections, disequilibrium, dizziness, and gastrointestional discomfort. Paroxysmal positive neurological phenomena are known to occur in MS. These include motor events such as paroxysmal tonic spasms. Sensory paroxysms also occur in MS. For example, trigeminal neuralgia (TN) is a defining example of intermittent positive sensory events in MS. The underlying pathophysiology of trigeminal neuralgia in MS likely involves focal demyelination of the pons at the nerve root entry zone Love and Coakham, 2001. Standard pharmacologic therapy for TN includes carbamazepine, oxcarbazepine, and baclofen, and lamotrigine Gronseth et al., 2008. Percutaneous glycerol rhizotomy Pickett et al., 2005
108
G.M. Thaera et al.
and posterior fossa microvascular decompression Broggi et al., 2010, Sandell and Eide, 2010 have been shown to be effective neurosurgical interventions for trigeminal neuralgia, even when symptomatic secondary to multiple sclerosis. Enhanced central nervous system (CNS) conduction promoted by dalfampridine could potentially lead to development or recurrence of positive neurological phenomena, including paroxysmal sensory, motor, or other CNS symptoms.
2.
Methods
We performed a retrospective review of medical records of all patients initiated on dalfampridine for gait impairment secondary to MS at our single academic institution during the time period March 2010 to April 2011. Each record was examined for incidences of positive neurologic symptoms while on dalfampridine. We evaluated the timing of onset and resolution of positive phenomena in prior history as well as related to initiation or cessation of dalfampridine.
3.
Results
76 MS patients were started on dalfampridine for multiple sclerosis. 45/76 patients (59%) were female. Five patients (19%) developed new positive paroxysmal symptoms (Table 1). Positive sensory symptoms of dysesthesias occurred in four patients (5.3%) Two patients experienced recurrence of severe lancinating face pain consistent with trigeminal neuralgia within 4 weeks of initiating dalfampridine (Table 2); the individual cases are further elaborated below. Neither patient experienced improvement in 25-foot walk time with dalfampridine; the medication was discontinued. However, neither patient experienced complete resolution of facial pain that had previously been in remission. A third patient with prior trigeminal neuralgia in sustained remission on oxcarbazepine experienced no paroxysmal sensory symptoms. Thus, 2/3 patients with prior TN experienced recurrence of facial pain in association with dalfampridine treatment. There were no de novo cases of trigeminal neuralgia with dalfampridine treatment. The two additional cases of positive sensory phenomena were de novo symptoms within four weeks of initiating dalfampridine. A 63 year old woman with secondaryprogressive MS developed new multifocal paroxysmal dysesthesias, and a 58 year old woman with relapsing-remitting MS developed severe bilateral leg pain. Both patients experienced full resolution of symptoms after stopping the medication. Finally, a 65 year-old woman with secondary Table 1 Positive paroxysmal phenomena in patients on dalfampridine for multiple sclerosis. Symptom
Number of patients
All positive neurologic phenomena Trigeminal neuralgia Multifocal paroxysmal dysthesias Bilateral leg pain Seizure
5/77 (6.6%) 2 1 1 1
Table 2 Demographic and clinical data on trigeminal neuralgia reactivated during initiation of dalfampridine. MS—multiple sclerosis. TN—trigeminal neuralgia. Patient 1 Age Gender Type of MS Onset of initial TN Distribution of initial TN Treatment for initial TN Change in TN Onset of recurrent TN Distribution of recurrent TN Treatment for recurrent TN
Patient 2
57 Male Secondary progressive
73 Female Secondary progressive 5 Years/8 months prior 4 Years prior
Left mandibular/right mandibular
Left maxillary, left mandibular
Carbamazepine, gabapentin, glycerol rhizotomy Mild -4 moderate Two weeks
Carbamazepine, gabapentin None -4 severe One month
Right mandibular
Left mandibular
Increase gabapentin
Glycerol rhizotomy
progressive MS developed new-onset seizure after seven doses of dalfampridine. She had no risk factors for seizures nor a family history of epilepsy. The medication was discontinued without further adverse effects. Thus, overall, positive neurologic symptoms associated with the initiation of dalfampridine resolved completely in 60% and partially in 40% after withdrawal of the medication. Case 1. Case 1 was a 57 year-old man with secondaryprogressive multiple sclerosis, on subcutaneous interferon beta-1a 44 microgram three times weekly. Five years before he was started on dalfampridine, he had left-sided trigeminal neuralgia in the mandibular division, treated with medication and two glycerol rhizotomies. Eight months prior, he developed similar lancinating right-sided mandibular facial pain; while a third glycerol rhizotomy was of no clear benefit, he was in sustained remission with pharmacologic therapy on carbamazepine 600 mg daily and gabapentin 600 mg daily His examination showed a spastic gait in the right lower extremity and worsening left leg weakness, so dalfampridine was initiated. Within two weeks of starting dalfampridine, right mandibular face pain had increased from mild to moderate, and the medication was discontinued. He had not noticed any significant improvement in his gait. The facial pain from TN persisted unchanged four days after cessation of dalfampridine and was treated with a sustained increase in gabapentin to 900 mg daily.
Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis
Fig. 1 Brain MRI of Case 2. T2 weighted image shows chronic lesion in the left pons, likely the etiology of trigeminal neuralgia in this patient.
Case 2. Case 2 was a 73-year old woman with secondaryprogressive multiple sclerosis, currently on no diseasemodifying therapy for MS but previously on intramuscular interferon beta-1a weekly. Four years preceding initiation of dalfampridine, she had developed left maxillary and mandibular facial pain consistent with trigeminal neuralgia in the setting of a new demyelinating lesion in the left pons (see Fig. 1). Her TN was in sustained remission for three years on carbamazepine 100 mg daily and gabapentin 1500 mg daily. Her 25-foot walk time was 10.3 seconds with a spastic-ataxic gait, and she was started on dalfampridine. Within four weeks of starting dalfampridine, she experienced frequent recurrence of trigeminal neuralgia with sharp left mandibular facial pain. Given lack of efficacy as well as recurrence of paroxysmal facial pain, the medication was stopped. Increases in carbamazepine and gabapentin were insufficient for pain control after dalfampridine was stopped. The patient did undergo a percutaneous glycerol rhizotomy with partial relief but continues to require gabapentin 1800 mg daily as monotherapy for pain control of trigeminal neuralgia.
4.
Discussion
In this retrospective case series, we described five patients with multiple sclerosis who experienced positive neurologic phenomena within four weeks of initiating dalfampridine for gait impairment secondary to multiple sclerosis. This study raises the potential concern that dalfampridine may be associated with de novo occurrence or recurrence of positive sensory symptoms. There is a known increased risk of seizure in patients with multiple sclerosis Koch et al., 2008 but also with use of all formulations of 4-aminopyridine. Increased axonal conduction from the potassium channel blockade promoted by dalfampridine may contribute to
109
positive neurologic phenomena such as those experienced in our series. Animal studies have shown that demyelinated dorsal root axons exposed to 4-aminopyridine fire repetitively in response to a single stimulus while ventral root axons only fire once Kocsis et al, 1986. This is a potential physiologic basis for increased sensory symptoms such as pain and paresthesias with blocking of potassium channels. Withdrawal of dalfampridine was insufficient to alleviate the facial pain in our two patients with recurrent trigeminal neuralgia, and additional pharmacologic therapy and neurosurgical intervention were required. Trigeminal neuralgia in both of our patients may have recurred due to a decreased threshold for excitatory action potentials in areas of focal demyelination with secondary ephaptic spread Obermann et al., 2007. Secondary central sensitization may play a role in explaining why recurrent trigeminal neuralgia did not completely resolve with discontinuation of dalfampridine, and thus additional interventions were required to treat the facial pain. In our retrospective case series, we highlighted patients with onset of positive sensory phenomena within four weeks of starting dalfampridine for gait impairment caused by multiple sclerosis. Patients should be cautioned that in addition to an increased risk of seizure, dalfampridine may be associated with positive sensory symptoms. Those with prior trigeminal neuralgia should be additionally cautioned that dalfampridine may trigger recurrence of paroxysmal facial pain and that further treatment may be needed.
Conflict of interest The authors have no conflicts of interest regarding this paper submission. There was no funding source required for this retrospective case series.
References Broggi G, Ferroli F, Franzini A, Servello D, Dones I. Microvascular decompression for trigeminal neuralgia: comments on a series of 250 cases, including 10 patients with multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 2000;68:59–64. Goodman AD, Brown TR. Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Sustained release of oral fampridine in multiple sclerosis: a randomized, double-blind, controlled trial. Lancet 2009; 373:732–8. Gronseth G, Cruccu G, Alksne J, et al. Practice parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review). Neurology 2008;71:1183–90. Koch M, Uyttenboogaart M, Polman S, De Keyser J. Seizures in multiple sclerosis. Epilepsia 2008;49:948–53. Kocsis JD, Bowe CM, Waxman SG. Different effects of 4-aminopyridine on sensory and motor fibers: pathogenesis of paresthesias. Neurology 1986;36:117–20. Love S, Coakham HB. Trigeminal neuralgia: Pathology and pathogenesis. Brain 2001;124:2347–60. Obermann N, Yoon M-S, Ese D, et al. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology 2007;69:835–41. Pickett GE, Bisnaire D, Ferguson GG. Percutanous retrogasserian glycerol rhizotomy in the treatment of tic doloreaux associated with multiple sclerosis. Neurosurgery 2005;56:537–45. Sandell T, Eide PK. The effect of microvascular decompression in patients with multiple sclerosis and trigeminal neuralgia. Neurosurgery 2010;67:749–54.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis Greg M. Thaeran, Dean M. Wingerchuk, Jonathan L. Carter Department of Neurology, Mayo Clinic, Scottsdale, Arizona Received 23 January 2013; received in revised form 11 May 2013; accepted 19 May 2013
KEYWORDS Multiple sclerosis; Dalfampridine; Sensation disorders; Seizures; Trigeminal neuralgia; Paroxysmal neurologic symptoms
1.
Abstract Objective: Review cases of positive neurologic phenomena initiated or worsened with dalfampridine in patients with multiple sclerosis.
Background: Oral, extended release dalfampridine (4-aminopyridine or 4-AP) is a potassiumchannel blocker approved for the treatment of gait impairment in multiple sclerosis (MS). The enhanced conduction along demyelinated axons promoted by dalfampridine could potentially lead to development of positive neurologic phenomena. Methods: We reviewed the medical records of patients who were started on dalfampridine for activation of positive sensory or motor symptoms. Results: Four of 76 patients (5.3%) developed positive sensory symptoms within one month of starting dalfampridine; one additional patient had new-onset seizure. Cessation of dalfampridine was insufficient to resolve symptoms in two patients with recurrent trigeminal neuralgia. Conclusions: Initiation of dalfampridine may be associated with initiation or recurrence of positive sensory symptoms in patients with multiple sclerosis. The increased axonal conduction from potassium channel blockade may contribute to this exacerbation of positive sensory phenomena. & 2013 Elsevier B.V. All rights reserved.
Background
Oral extended-release dalfampridine, also known as 4aminopyridine or 4-AP, is a blocker of voltage-gated potassium channels. This medication has shown efficacy in treating gait impairment related to multiple sclerosis (MS) Goodman et al., 2009. Dalfampridine acts to enhance electrical conduction across demyelinated segments of axons affected by MS. The most serious potential adverse reaction is an increased risk for seizures, which is likely related to blockade n
Corresponding author. Tel.: +1 480 301 8100 E-mail address: [email protected] (G.M. Thaera).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.05.003
of potassium channels. Additional side effects include an increased incidence of urinary tract infections, disequilibrium, dizziness, and gastrointestional discomfort. Paroxysmal positive neurological phenomena are known to occur in MS. These include motor events such as paroxysmal tonic spasms. Sensory paroxysms also occur in MS. For example, trigeminal neuralgia (TN) is a defining example of intermittent positive sensory events in MS. The underlying pathophysiology of trigeminal neuralgia in MS likely involves focal demyelination of the pons at the nerve root entry zone Love and Coakham, 2001. Standard pharmacologic therapy for TN includes carbamazepine, oxcarbazepine, and baclofen, and lamotrigine Gronseth et al., 2008. Percutaneous glycerol rhizotomy Pickett et al., 2005
108
G.M. Thaera et al.
and posterior fossa microvascular decompression Broggi et al., 2010, Sandell and Eide, 2010 have been shown to be effective neurosurgical interventions for trigeminal neuralgia, even when symptomatic secondary to multiple sclerosis. Enhanced central nervous system (CNS) conduction promoted by dalfampridine could potentially lead to development or recurrence of positive neurological phenomena, including paroxysmal sensory, motor, or other CNS symptoms.
2.
Methods
We performed a retrospective review of medical records of all patients initiated on dalfampridine for gait impairment secondary to MS at our single academic institution during the time period March 2010 to April 2011. Each record was examined for incidences of positive neurologic symptoms while on dalfampridine. We evaluated the timing of onset and resolution of positive phenomena in prior history as well as related to initiation or cessation of dalfampridine.
3.
Results
76 MS patients were started on dalfampridine for multiple sclerosis. 45/76 patients (59%) were female. Five patients (19%) developed new positive paroxysmal symptoms (Table 1). Positive sensory symptoms of dysesthesias occurred in four patients (5.3%) Two patients experienced recurrence of severe lancinating face pain consistent with trigeminal neuralgia within 4 weeks of initiating dalfampridine (Table 2); the individual cases are further elaborated below. Neither patient experienced improvement in 25-foot walk time with dalfampridine; the medication was discontinued. However, neither patient experienced complete resolution of facial pain that had previously been in remission. A third patient with prior trigeminal neuralgia in sustained remission on oxcarbazepine experienced no paroxysmal sensory symptoms. Thus, 2/3 patients with prior TN experienced recurrence of facial pain in association with dalfampridine treatment. There were no de novo cases of trigeminal neuralgia with dalfampridine treatment. The two additional cases of positive sensory phenomena were de novo symptoms within four weeks of initiating dalfampridine. A 63 year old woman with secondaryprogressive MS developed new multifocal paroxysmal dysesthesias, and a 58 year old woman with relapsing-remitting MS developed severe bilateral leg pain. Both patients experienced full resolution of symptoms after stopping the medication. Finally, a 65 year-old woman with secondary Table 1 Positive paroxysmal phenomena in patients on dalfampridine for multiple sclerosis. Symptom
Number of patients
All positive neurologic phenomena Trigeminal neuralgia Multifocal paroxysmal dysthesias Bilateral leg pain Seizure
5/77 (6.6%) 2 1 1 1
Table 2 Demographic and clinical data on trigeminal neuralgia reactivated during initiation of dalfampridine. MS—multiple sclerosis. TN—trigeminal neuralgia. Patient 1 Age Gender Type of MS Onset of initial TN Distribution of initial TN Treatment for initial TN Change in TN Onset of recurrent TN Distribution of recurrent TN Treatment for recurrent TN
Patient 2
57 Male Secondary progressive
73 Female Secondary progressive 5 Years/8 months prior 4 Years prior
Left mandibular/right mandibular
Left maxillary, left mandibular
Carbamazepine, gabapentin, glycerol rhizotomy Mild -4 moderate Two weeks
Carbamazepine, gabapentin None -4 severe One month
Right mandibular
Left mandibular
Increase gabapentin
Glycerol rhizotomy
progressive MS developed new-onset seizure after seven doses of dalfampridine. She had no risk factors for seizures nor a family history of epilepsy. The medication was discontinued without further adverse effects. Thus, overall, positive neurologic symptoms associated with the initiation of dalfampridine resolved completely in 60% and partially in 40% after withdrawal of the medication. Case 1. Case 1 was a 57 year-old man with secondaryprogressive multiple sclerosis, on subcutaneous interferon beta-1a 44 microgram three times weekly. Five years before he was started on dalfampridine, he had left-sided trigeminal neuralgia in the mandibular division, treated with medication and two glycerol rhizotomies. Eight months prior, he developed similar lancinating right-sided mandibular facial pain; while a third glycerol rhizotomy was of no clear benefit, he was in sustained remission with pharmacologic therapy on carbamazepine 600 mg daily and gabapentin 600 mg daily His examination showed a spastic gait in the right lower extremity and worsening left leg weakness, so dalfampridine was initiated. Within two weeks of starting dalfampridine, right mandibular face pain had increased from mild to moderate, and the medication was discontinued. He had not noticed any significant improvement in his gait. The facial pain from TN persisted unchanged four days after cessation of dalfampridine and was treated with a sustained increase in gabapentin to 900 mg daily.
Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis
Fig. 1 Brain MRI of Case 2. T2 weighted image shows chronic lesion in the left pons, likely the etiology of trigeminal neuralgia in this patient.
Case 2. Case 2 was a 73-year old woman with secondaryprogressive multiple sclerosis, currently on no diseasemodifying therapy for MS but previously on intramuscular interferon beta-1a weekly. Four years preceding initiation of dalfampridine, she had developed left maxillary and mandibular facial pain consistent with trigeminal neuralgia in the setting of a new demyelinating lesion in the left pons (see Fig. 1). Her TN was in sustained remission for three years on carbamazepine 100 mg daily and gabapentin 1500 mg daily. Her 25-foot walk time was 10.3 seconds with a spastic-ataxic gait, and she was started on dalfampridine. Within four weeks of starting dalfampridine, she experienced frequent recurrence of trigeminal neuralgia with sharp left mandibular facial pain. Given lack of efficacy as well as recurrence of paroxysmal facial pain, the medication was stopped. Increases in carbamazepine and gabapentin were insufficient for pain control after dalfampridine was stopped. The patient did undergo a percutaneous glycerol rhizotomy with partial relief but continues to require gabapentin 1800 mg daily as monotherapy for pain control of trigeminal neuralgia.
4.
Discussion
In this retrospective case series, we described five patients with multiple sclerosis who experienced positive neurologic phenomena within four weeks of initiating dalfampridine for gait impairment secondary to multiple sclerosis. This study raises the potential concern that dalfampridine may be associated with de novo occurrence or recurrence of positive sensory symptoms. There is a known increased risk of seizure in patients with multiple sclerosis Koch et al., 2008 but also with use of all formulations of 4-aminopyridine. Increased axonal conduction from the potassium channel blockade promoted by dalfampridine may contribute to
109
positive neurologic phenomena such as those experienced in our series. Animal studies have shown that demyelinated dorsal root axons exposed to 4-aminopyridine fire repetitively in response to a single stimulus while ventral root axons only fire once Kocsis et al, 1986. This is a potential physiologic basis for increased sensory symptoms such as pain and paresthesias with blocking of potassium channels. Withdrawal of dalfampridine was insufficient to alleviate the facial pain in our two patients with recurrent trigeminal neuralgia, and additional pharmacologic therapy and neurosurgical intervention were required. Trigeminal neuralgia in both of our patients may have recurred due to a decreased threshold for excitatory action potentials in areas of focal demyelination with secondary ephaptic spread Obermann et al., 2007. Secondary central sensitization may play a role in explaining why recurrent trigeminal neuralgia did not completely resolve with discontinuation of dalfampridine, and thus additional interventions were required to treat the facial pain. In our retrospective case series, we highlighted patients with onset of positive sensory phenomena within four weeks of starting dalfampridine for gait impairment caused by multiple sclerosis. Patients should be cautioned that in addition to an increased risk of seizure, dalfampridine may be associated with positive sensory symptoms. Those with prior trigeminal neuralgia should be additionally cautioned that dalfampridine may trigger recurrence of paroxysmal facial pain and that further treatment may be needed.
Conflict of interest The authors have no conflicts of interest regarding this paper submission. There was no funding source required for this retrospective case series.
References Broggi G, Ferroli F, Franzini A, Servello D, Dones I. Microvascular decompression for trigeminal neuralgia: comments on a series of 250 cases, including 10 patients with multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 2000;68:59–64. Goodman AD, Brown TR. Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Sustained release of oral fampridine in multiple sclerosis: a randomized, double-blind, controlled trial. Lancet 2009; 373:732–8. Gronseth G, Cruccu G, Alksne J, et al. Practice parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review). Neurology 2008;71:1183–90. Koch M, Uyttenboogaart M, Polman S, De Keyser J. Seizures in multiple sclerosis. Epilepsia 2008;49:948–53. Kocsis JD, Bowe CM, Waxman SG. Different effects of 4-aminopyridine on sensory and motor fibers: pathogenesis of paresthesias. Neurology 1986;36:117–20. Love S, Coakham HB. Trigeminal neuralgia: Pathology and pathogenesis. Brain 2001;124:2347–60. Obermann N, Yoon M-S, Ese D, et al. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology 2007;69:835–41. Pickett GE, Bisnaire D, Ferguson GG. Percutanous retrogasserian glycerol rhizotomy in the treatment of tic doloreaux associated with multiple sclerosis. Neurosurgery 2005;56:537–45. Sandell T, Eide PK. The effect of microvascular decompression in patients with multiple sclerosis and trigeminal neuralgia. Neurosurgery 2010;67:749–54.
