By Marcello Cherchi, MD PhD
For patients
Periodic alternating nystagmus (PAN) is an abnormal wiggling movement of the eyes that switches direction every few minutes. Most cases begin in adulthood, though occasionally it begins in early childhood. Some cases of PAN appear to occur spontaneously (without any underlying cause), while other cases seem to be associated with specific diseases. If your doctor suspects PAN, they may check several tests of eye movement function, and a brain MRI. There are no good treatments, though some patients benefit from baclofen.
For clinicians
Overview
Periodic alternating nystagmus (PAN) is spontaneous horizontal nystagmus that alternates in direction, whose cycles are usually 2 – 4 minutes. Most cases of PAN are acquired; some are congenital. Most cases are spontaneous; rare familial cases have been reported. The underlying pathophysiology is unknown, though the idea of a slowly oscillating null point has been proposed. Patients with PAN often complain of oscillopsia. PAN can occur in isolation, though some cases occur in the context of other pathologies, such as encephalitis, diseases affecting the cerebellum (neoplasm, infarct, demyelination, Chiari malformation) or posterior fossa (arachnoid cyst, posterior reversible encephalopathy syndrome), albinism, or ataxias (Friedreich’s ataxia, spinocerebellar ataxia). Rare cases appear as adverse effects of medications (lithium, primidone, phenobarbital). Oculography is useful for documenting and characterizing the ocular motor abnormality. Rotatory chair testing may show elevated gain on slow harmonic acceleration. In a patient with PAN it is sensible to check a brain MRI to identify structural causes (e.g., Chiari malformation, neoplasm) and acute causes (e.g., infarction, demyelination). In cases with irreversible underlying causes, an attempt at treatment with baclofen is reasonable.
Introduction
Periodic alternating nystagmus (PAN) is spontaneous horizontal nystagmus that alternates in direction.
The Figure below, from Baloh and colleagues (Baloh et al. 1976) shows a tracing of horizontal eye movements from a patient with PAN. In horizontal eye movement tracings, by convention, an upward deflection represents eye movement towards the patient’s right, and a downward deflection represents eye movement towards the patient’s left.
The first part of this tracing (top) shows spontaneous right beat nystagmus. The middle tracing shows that the right beat nystagmus diminishes and stops, then there is a period of no spontaneous eye movement, then there begins to appear spontaneous left beat nystagmus. The bottom tracing shows that this spontaneous left beat nystagmus augments.
The Video below, from https://www.youtube.com/watch?v=AapjodNpEz0 (accessed 4/2/23), shows an example of PAN.
Epidemiology
PAN is often an acquired disorder, though it can also occur as a form of congenital nystagmus (Shallo-Hoffmann et al. 1999; Shallo-Hoffmann and Riordan-Eva 2001).
Genetics
Familial patterns of PAN have been reported (Hertle et al. 2005), but the genetic contribution to PAN is unknown.
Pathophysiological mechanism of disease
The underlying pathophysiology of PAN is unknown. Several mechanisms have been proposed.
Several investigators have suggested a slowly oscillating shift of the null point as the likely mechanism (Daroff and Dell’Osso 1974; Robb 1972).
Based on analysis of abnormalities observed in saccades and smooth pursuit during the nystagmus-free intervals of PAN, Meienberg and Hoyt postulated cerebellar disinhibition as the mechanism of PAN (Meienberg and Hoyt 1980). Rudge and Leech further suggested that PAN may be due to, “alternating activity of the vestibular nuclei on either side of the brain-stem as a result of a removal of cerebellar inhibition, and that this caused periodic shifts in the null region of Daroff and Dell’Osso” (Rudge and Leech 1976).
Leigh and colleagues offer a control systems analysis model of PAN and propose that, “PAN arises from (1) an instability in the brain-stem neural networks that generate slow phases of vestibular and optokinetic nystagmus, (2) the action of an adaptive network that normally acts to null prolonged, inappropriate nystagmus, and (3) an inability to use retinal-error-velocity information” (Leigh et al. 1981).
Furman and colleagues (Furman et al. 1989) propose a control systems analysis model of PAN. In a subsequent piece, Furman and colleagues (Furman et al. 1990) concluded that, “PAN is caused by an instability in the velocity storage element, a hypothetical neural circuit that perseverates the eye movement response to both vestibular and optokinetic stimulation. Further, we postulate that PAN may be caused by lesions of the cerebellar uvula and nodulus or their connections with the brainstem vestibular nuclei.”
Although most investigators postulate a neurological mechanism for PAN, there have also been reports of PAN occurring with peripheral (labyrinthine) disease. For example, Murofushi and colleagues described PAN in a patient with Ménière’s disease (Murofushi et al. 2008); Kim and colleagues described PAN in patients with Ménière’s disease, acute labyrinthitis and vestibular schwannoma; Taki and colleagues described PAN during caloric stimulation (Taki et al. 2014). The mechanism by which peripheral labyrinthine disease or stimulation could provoke PAN is unknown.
Clinical presentation
Patients with PAN commonly complain of oscillopsia.
Physical examination
Aside from the ocular motor abnormalities (see below), an individual with PAN who is otherwise healthy should have a normal physical examination
Ocular motor examination
PAN can occur as an isolated ocular motor manifestation, though it can also occur in association with other ocular motor abnormalities, such as spontaneous down beat nystagmus (Keane 1974) and pendular see-saw nystagmus (Jeong et al. 2009).
The periodicity of PAN — meaning the time from the start of the phase of nystagmus beating in one direction, through the null period, through the phase of nystagmus beating in the other direction — is variable. Baloh and colleagues (Baloh et al. 1976) state that the periodicity “cycle length has varied from 1 to 6 min[utes] with null periods varying from 2 to 20 s[econds].”
Testing: vestibular
Furman and colleagues studied 4 PAN patients with rotatory chair testing and observed that on slow harmonic acceleration:
“As in normal subjects, the gain of the VOR [vestibulo-ocular reflex] of the patients with PAN increases with increasing frequency. However, in general, the patients’ gain was greater than normal” (Furman et al. 1990).
In addition they reported that:
“The phase of patients’ horizontal VOR shows a surprising result in that their phase lead at 0.05 Hz was less than the average for normal (in 3 out of 4 cases), while at 0.0025 Hz, each patient’s phase lead was much greater than normal. This pattern of abnormality has not been reported previously for any vestibular disorder. Phase leads at 0.0025 Hz have not been reported previously for any human subjects” (Furman et al. 1990).
Imaging
Imaging in patients with isolated PAN is usually normal, though helps to exclude competing diagnoses.
Acute acquired PAN usually warrants obtaining a brain MRI as it can result from infarction of the cerebellar nodulus, as shown in the Figure below from Jeong and colleagues (Jeong et al. 2007).
Histopathology
Baloh and colleagues (Baloh et al. 1976) reviewed autopsies of 3 patients with PAN. The first case involved a cyst of the fourth ventricle; the second case involved a Chiari malformation; the third case involved multiple sclerosis (Keane 1974). Baloh and colleagues state that, “in each [case], multiple regions of the brain-stem have been involved.” Furman and colleagues (Furman et al. 1990) cited several additional autopsy studies (Karp and Rorke 1975; Susac and Henry 1975); the study by Karp and Rorke reported the case of an 11-year-old girl with an astrocytoma involving the vestibular nuclei at the pontomedullary junction on one side (Karp and Rorke 1975).
Differential diagnosis
While PAN is an interesting ocular motor finding, in some cases it is associated with a diagnosable disease. Baloh and colleagues (Baloh et al. 1976) list a variety of conditions with which PAN has occurred, including encephalitis, brainstem ischemia, demyelinating disease, syringobulbia, syphilis and trauma. Furman and colleagues (Furman et al. 1990) list additional associated diagnoses including spinocerebellar degeneration, posterior fossa neoplasm, posterior fossa arachnoid cyst and cryptococcal infection. There are additionally case reports of PAN occurring in the context of acute lesions of the cerebellar nodulus (Jeong et al. 2007; Oh et al. 2006), albinism (Guyer and Lessell 1986), posterior reversible encephalopathy syndrome (Mackay et al. 2014), Chiari malformation (Korres et al. 2001), Friedreich’s ataxia (Gorman and Brock 1950; Gorman et al. 1950), spinocerebellar ataxia type 6 (Hashimoto et al. 2003), multiple sclerosis (Matsumoto et al. 2001) and epilepsy (Moster and Schnayder 1998). It also appears that PAN can be induced by certain medications such as lithium (Lee and Lessell 2003; Rust et al. 2016) and primidone/phenobarbital (Schwankhaus et al. 1989).
Treatment
Several papers have observed that baclofen can improve PAN (DiBartolomeo and Yee 1988) whether it is acquired (Halmagyi et al. 1980; Isago et al. 1985) or congenital (Comer et al. 2006; Solomon et al. 2002).
Other treatments are based largely on case reports.
Lee and colleagues (Lee et al. 2016) reported improvement of PAN with amantadine.
Argente-Escrig and colleagues (Argente-Escrig et al. 2017) reported improvement of PAN in a patient treated with intravenous immunoglobulin, and postulated ex juvantibus an autoimmune mechanism.
Kumar and colleagues (Kumar et al. 2009) reported improvement of PAN with memantine.
Surgery on extraocular muscles has also been attempted as treatment for PAN (Mimura et al. 2014; Thomas et al. 1996).
Prognosis
The prognosis of PAN depends on the underlying etiology. There are very few reversible causes of PAN (e.g., medication toxicity). For the remainder, prognosis is guarded, and treatment will depend on the etiology; for example, disease modifying therapy for multiple sclerosis, or resection for posterior fossa tumor.
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