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Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis

Multiple Sclerosis and Related Disorders, 1, 3, pages 107 - 109

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 potassium-channel 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.

Highlights

 

  • 77 MS patients were started on dalfampridine.
  • Four of 77 patients (5.3%) experienced positive sensory symptoms within 4 weeks.
  • Two patients had recurrent trigeminal neuralgia requiring additional interventions.
  • One patient developed new-onset seizure after seven doses of dalfampridine.

Keywords: Multiple sclerosis, Dalfampridine, Sensation disorders, Seizures, Trigeminal neuralgia, Paroxysmal neurologic symptoms.

1. Background

Oral extended-release dalfampridine, also known as 4-aminopyridine 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 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 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.

Table 1 Positive paroxysmal phenomena in patients on dalfampridine for multiple sclerosis.

Symptom Number of patients
All positive neurologic phenomena 5/77 (6.6%)
Trigeminal neuralgia 2
Multifocal paroxysmal dysthesias 1
Bilateral leg pain 1
Seizure 1

Table 2 Demographic and clinical data on trigeminal neuralgia reactivated during initiation of dalfampridine. MS—multiple sclerosis. TN—trigeminal neuralgia.

  Patient 1 Patient 2
Age 57 73
Gender Male Female
Type of MS Secondary progressive Secondary progressive
Onset of initial TN 5 Years/8 months prior 4 Years prior
Distribution of initial TN Left mandibular/right mandibular Left maxillary, left mandibular
Treatment for initial TN Carbamazepine, gabapentin, glycerol rhizotomy Carbamazepine, gabapentin
Change in TN Mild -> moderate None -> severe
Onset of recurrent TN Two weeks One month
Distribution of recurrent TN Right mandibular Left mandibular
Treatment for recurrent TN Increase gabapentin Glycerol rhizotomy

The two additional cases of positive sensory phenomena were de novo symptoms within four weeks of initiating dalfampridine. A 63 year old woman with secondary-progressive 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 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 secondary-progressive 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.

Case 2 -

Case 2 was a 73-year old woman with secondary-progressive multiple sclerosis, currently on no disease-modifying 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.

 

gr1

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.

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 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

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  • Kocsis et al., 1986 JD Kocsis, CM Bowe, SG. Waxman. Different effects of 4-aminopyridine on sensory and motor fibers: pathogenesis of paresthesias. Neurology. 1986;36:117-120
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Footnotes

Department of Neurology, Mayo Clinic, Scottsdale, Arizona

lowast Corresponding author. Tel.: +1 480 301 8100