Vestibular and hearing manifestations of phenytoin toxicity: A retrospective series.

Abstract

We undertook a study to identify the vestibular and hearing abnormalities associated with phenytoin toxicity. Since October 1977, 23 patients with phenytoin toxicity have been referred to the Department of Otorhinolaryngology by the Department of Neurology for electrooculographic (EOG) evaluation. (There have been no cases of serious phenytoin toxicity seen in our department since August 1989.) In addition to EOG, all patients had undergone otoscopic, audiometric, and neurologic examinations. We found that the most common pathologic findings detected by EOG were abnormalities in pursuit tracking. The most common signs found on clinical exploration were cerebellar dysfunction and facial palsy. EOG findings in patients with phenytoin toxicity are compatible with cerebellar disease.

Introduction

Phenytoin (diphenylhydantoin) is one of the most widely used anticonvulsants, particularly in the acute and chronic management of epilepsy in children and adults. This drug is remarkably free of serious side effects, [1] although toxic blood levels can cause adverse neurotologic effects. [2] Long-term therapy has been reported to cause cerebellar atrophy in humans. [3] Adverse effects in experimental animals have included a loss of Purkinje's cells, edema of Bergmann's glial cell layer, and degenerative cell changes. [4] The primary signs and symptoms of toxicity are shown in table 1. [1,5-13] Generally, all these effects are reversible and disappear after a reduction in dosage or cessation of the drug, except for chronic cerebellar ataxia secondary to long-term phenytoin intake, which is considered to be irreversible. [2] The aim of our study was to identify the vestibular and hearing abnormalities associated with phenytoin toxicity.

Materials and methods

Since October 1977, 23 patients with phenytoin toxicity have been referred to the Department of Otorhinolaryngology by the Department of Neurology for electrooculographic (EOG) evaluation. (There have been no cases of serious phenytoin toxicity seen in our department since August 1989.) The diagnosis of phenytoin toxicity had been made in the Department of Neurology according to the presence of certain clinical manifestations (table 2). According to our retrospective chart review, the 15 female and 8 male patients ranged in age from 13 to 64 years (mean: 34.6). Otoscopy, audiometry, a basic neurologic exploration, and an EOG examination had been performed on all subjects. Since 1985, it has been possible to obtain blood phenytoin levels at our hospital, and this information was included in the records of 8 patients who had been seen after 1985.

During the EOG examination, eye movements were registered by a Grass polygraph (model 79D) and DC register, with an upper cutoff frequency of 75 Hz. Monocular horizontal eye movements were measured with surface electrodes fixed medially to the inner canthus and laterally to the outer canthus of each eye. A pair of vertically fixed electrodes attached over the eyebrow and below the lower eyelid was used to detect blink artifacts and vertical nystagmic components. Each patient was evaluated for saccades, spontaneous nystagmus, response to rotational and positional tests, vestibulo-ocular reflex suppression, optokinetic nystagmus, and pursuit tracking. Saccades were studied with an alternating luminous point that was driven by an OK4 generator (ServoMed). Spontaneous nystagmus was registered with closed eyes. Rotational tests were conducted with a diminished pendular stimulus; at the same time, vestibulo-ocular reflex suppression was registered with the patient's gaze fixed on a point that moved simultaneously w ith the pendular motion. Optokinetic nystagmus was stimulated with a rotating drum that was electrically controlled at two different speeds: 30[degrees] and 150[degrees]/sec. All results were analyzed by the Department of Research at our institution.

Results

We found no hearing impairment in any of these patients. The most common clinical findings were cerebellar signs and facial palsy. On EOG, the most common pathologic findings were abnormalities in pursuit tracking. We saw no case of diplopia or impairment of the IIIrd, IVth, or VIth cranial nerves. Details:

* Only 1 patient had an abnormal otoscopic examination (4.4%).

* There were 13 vestibular and auditory complaints: 8 cases of dizziness (34.8%), 3 of vertigo (13.0%), and 2 of hypoacusis (8.7%). There were no cases of algiacusis or tinnitus.

* The results of clinical exploration are shown in table 3.

* EOG revealed that 1 patient (4.4%) had dysmetric saccades; saccades were normal in the remaining patients.

* Spontaneous nystagmus was found in 3 patients (13.0%); 2 had periodic alternating nystagmus, and 1 had gaze-evoked horizontal nystagmus.

* During the rotational test, abnormalities were registered in 7 patients (30.4%); 2 had a left preponderance, 1 had bilateral hyperreflexia, 3 had bilateral hyporeflexia, and 1 had an atypical morphologic pattern. Only 1 patient exhibited alterations during the positional test; this patient had a type II recording according to Arslan's method.

* Vestibulo-ocular reflex suppression was diminished in 3 patients (13.0%). No patient had an absence of vestibulo-ocular reflex suppression.

* During optokinetic nystagmus testing, unilateral and bilateral impairments of the passive component were registered in 2(8.7%) and 7 (30.4%) patients, respectively.

* Pursuit tracking showed an ataxic appearance in 6 patients (26.1%) and a saccadic appearance in 6.

In the charts of the 8 patients who were seen after 1985, the only information with respect to blood phenytoin levels was whether levels were higher than 30 [micro]g/ml. Therefore, it was not possible to calculate statistical correlations between blood levels and vestibular responses.

Eight cases were revised 1 year later, and all of these patients had the same EOG findings that they had during their first exploration.

Discussion

Phenytoin use is remarkably free of complications. [1] Reports of serious side effects, including mental symptoms and seizures, have usually been confined to patients who took a single large dose, either accidentally or intentionally. Deaths have been reported occasionally in adults [14] and children. [15,16] In patients who do have high serum phenytoin levels, nystagmus appears at a concentration of about 20 [micro]g/ml and ataxia at 30 [micro]g/ml. [17] Today, toxicity is rare because we have a better understanding of phenytoin's pharmacologic characteristics. For example, although there is great variability in neurologically and neurotologically toxic serum levels, there have been no cases of serious toxicity in our department since 1989. This fact underscores the clear improvement in our clinical management of phenytoin.

The most common finding in our series was alteration in pursuit tracking. However, no conclusions regarding typical oculomotor findings have been reported in the current literature because of the small number of cases reported in each article. [7,9] To our knowledge, no large series has been reported to date.

Videonystagmography is the current method of choice for evaluating ocular movements in the neurotologic practice. EOG examination was employed in this study because these patients had been evaluated before videonystagmography had become completely developed. Although we were not able to obtain quantitative measurements of alterations in ocular movement, we believe that qualitative findings also have great clinical value.

On the basis of experimental data, the structure of the central nervous system that is most affected by phenytoin poisoning is the cerebellum. [4] Our EOG findings of cerebellar dysfunction support this hypothesis. The evidence for cerebellar damage is supported by two experimental findings: (1) the increase in the postsynaptic potentials produced by gamma aminobutyric acid in the vestibulooculomotor system and (2) the increase in the rate of Purkinje's cell discharge at the cerebellar flocculus. [11] Deficits in some cranial nerves (V and VII) can also occur, so facial paralysis and impairment of the Vth cranial nerve are not considered to be rare in phenytoin toxicity.

Audiometric alterations (presbyacusis) are not linked to phenytoin toxicity, and hearing does not appear to be affected by toxic phenytoin levels. Neither of these findings has been previously reported. Unlike Manlapaz, [6] we found no case of abducens nerve palsy in our patients.

Ever since the first reports of phenytoin toxicity, dialysis (peritoneal and/or hemodialysis) and bed rest have been advocated as a useful treatment)8 Although death associated with phenytoin toxicity is rare, the possibility justifies such aggressive management. [14-16]

From the Department of Otorhinolaryngology (Dr. De Diego, Dr. Prim, Dr. Marcos, Dr. De Sarria, and Dr. Gavilan) and the Department of Neurology (Dr. Arpa), La Paz Hospital, Autonomous University, Madrid.

References

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(3.) McLain LW, Martin JT, Allen JH. Cerebellar degeneration due to chronic phenytoin therapy. Ann Neurol 1980;7:18-23.

(4.) Kokenge R, Kutt H, McDowell F. Neurological sequelac following Dilantin overdose in a patient and in experimental animals. Neurology 1965;15:823-9.

(5.) Berger JR, Kovacs AG. Downbeat nystagmus with phenytoin. J Clin Neuroophthalmol 1982;2:209-l1.

(6.) Manlapaz JS. Abducens nerve palsy in dilantin intoxication. J Pediat, St. Louis 1959;55:73-7.

(7.) Blair AA, Hallpike JF, Lascelles PT, Wingate DL. Acute diphenylhydantoin and primidone poisoning treated by peritoneal dialysis. J Neurol Neurosurg Psychiatry 1968;31:520-3.

(8.) Campbell WW. Periodic alternating nystagmus in phenytoin intoxication. Arch Neurol 1980;37:178-80.

(9.) Nozue M, Mizuno M, Kaga K. Neurotological Findings in diphenylhydantoine intoxication. Ann Otol Rhinol Laryngol 1973;82:389-94.

(10.) Orth DN, Almeida H, Walsh FB, Honda M. Ophthalmoplegia resulting from diphenylhydantoin and primidone intoxication. JAMA 1967;201:485-7.

(11.) Spector RH, Davidoff RA, Schwartzman RJ. Phenytoin-induced ophthalmoplegia. Neurology 1976;26:1031-4.

(12.) Choonara IA, Rosenbloom L. Focal dystonic reaction to phenytom. Dev Med Child Neurol 1984;26:677-8.

(13.) Howrie DL, Crumrine PK. Phenytoin-induced movement disorder associated with intravenous administration for status epilepticus. Clin Pediatr (Phila) 1985;24:467-9.

(14.) Tichner JB, Enselberg CD. Suicidal sodium diphenylhydantoin poisoning. N Engl J Med 195l;245:723-5.

(15.) Schmeisser M. Todliche Vergiftung mit Zentropil beim Kind. Kinderatzl. Praxis 1952;20:158-66.

(16.) LaubsclierFA. Fatal diphepylhydantoin poisoning. A case report. JAMA 1966;198:1120-l.

(17.) Buchthal F, Svensmark O, Schiller PJ. Clinical and electro encephalographic correlations with serum levels of diphenylhydantoin. AMA Arch Neurol 1960;2:624-30.

(18.) Sebreiner GE. The role of hemodialysis (artificial kidney) in acute poisoning. AMA Arch Int M 1958;102:896-913.

Table 1. Neurologic and neurotologic manifestations of phenytoin
toxicity 1,5-13
Ataxia                Oculogyria
Diplopia              Orofacial dyskinesia
Divergent strabismus  Total ophthalmoplegia
Dysarthria            Transient abduction paresis
Headache              Tremor
Nystagmus *           Vertigo
(*)Includes gaze-evoked horizontalnystagmus, periodic alternating
nystagmus, alternations of optokineticnystagmus, downbeat nystagmus,
and impaired smooth pursuit eyemovements.

Table 2. Diagnostic criteria for acute and chronic phenytoin toxicity

Acute

Ataxia

Dysarthria

Dysdiadochokinesia

Dysmetria

Pathologic Romberg test

Spontaneous nystagmus

Chronic

Hyporeflexia

Sensitive neuropathy

Table 3. Clinical manifestations in our series of 23 patients
                                n (%)
Cerebellar signs
 Dysdiadochokinesia            5 (21.7)
 Dysmetria                     6 (26.1)
Abnormal audiometry *          4 (17.4)
Abnormal Romberg test          6 (26.1)
Abnormal tandem test           4 (17.4)
Abnormal Unterberger's test    5 (21.7)
IIIrd cranial nerve paralysis     0
IVth cranial nerve paralysis      0
Vth cranial nerve impairment
 Corneal anesthesia            1 (4.4)
 Facial anesthesia             1 (4.4)
VIth cranial nerve paralysis      0
VIIth cranial nerve paralysis  2 (8.7)
(*)All 4 patients had presbyacusis.