Diagnostic approach in atypical optic neuropathy

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Optic neuropathy regroups a broad spectrum of ophthalmological or systemic conditions that can affect the optic nerve.The pathophysiological mechanisms of optic neuropathies vary widely including inflammatory, traumatic, ischemic, autoimmune, genetic, or toxic mechanisms. As the prognosis and the therapeutic strategy can dramatically differ according to the mechanism involved, it is crucial to determine as precisely as possible the etiology of the optic neuropathy. There are important steps in the diagnostic approach of optic neuropathies: the first step is to identify the optic nerve as the cause of the symptoms reported by the patient. This step, although easy in most patients, can be more challenging in certain cases, leading to considerable diagnostic delay. The second step is to narrow the field of possible causes of optic neuropathy with a detailed history and a thorough clinical examination. This second step is essential to target the most appropriate medical work-up, and to determine precisely the cause of the optic neuropathy. 

Risk Factors

The incidence of optic neuritis is highest in populations located at higher latitudes (Northern United States; Northern and Western Europe; New Zealand and Southern Australia) compared with geographic locations closer to the equator. In the United States of America, studies have estimated the annual incidence of optic neuritis as 5 to 6.4 per 100 000, with a prevalence of 115 per 100 000. 


Inflammatory optic neuropathies, commonly known as optic neuritises, are acquired inflammatory diseases of the optic nerve which mainly concern young adults. Their diagnosis is clinical. They associate a variable drop in the visual acuity, unilateral most frequently, with rapidly progressive manifestation and ocular pain increased by the movements of the eyeball. Optic neuritises are secondary, in most cases, to a demyelinating inflammatory disease of the optic nerve within the context of multiple sclerosis, and have a clinical presentation said to be typical. To determine the etiology of a first episode of optic neuritis, it relies on the magnetic resonance imaging, a test which is most often the only necessary one for a typical optic neuritis. On the other hand, in case of an inflammatory optic neuropathy, it is necessary to carry out an evaluation on a larger scale in order to search for rarer etiologies and eliminate differential diagnoses.

Physical examination

A 47 -Year-old man reported acute visual acuity decrease in his both eyes for three days. In his general medical history, no interesting findings were found (myopia with no wearing glasses). He did no relate neurological or general symptoms.

At admission, he had light perception in the right eye and absence of light perception in the left eye. Ocular motility was normal. Slit lamp examination showed non-reflective mydriasis. Intraocular pressure was 14 in both eyes. Fundus examination showed a bilateral optic disc swelling(Figure1).Figure 1: Bilateral Optic Swelling

Diagnostic procedures

Optic coherence tomography of both eyes was normal . Fluorescein Angiogram disclosed a bilateral dye leakage in both optic nerves confirming bilateral papillitis (Figure 3). The Visual Evoked Potentials showed amplitude decreased (Figure 4).

Neurological examination was normal. The brain MRI confirmed the presence of lesions, which was hypointense on diffusion-weighted images, hyperintense on T2-weighted images and hypointense on T1-weighted images, with no contrast enhancement after gadolinium administration. No mass effect was observed. These lesions were strictly limited to the white matter suggesting a demyelinating disease (Figure 5). Spinal MRI was normal.

Figure: 3 Figure: 4 Figure: 5

Laboratory test

Biological assessment found normal and we performed supplementary tests with HIV serology and antibodies directed against aquaporin 4. There was no renal failure or inflammation. 

Differential diagnosis

 This young man presents a pathology with pure neuro-ophthalmological tropism. We had any argument for systemic inflammatory disease (sarcoidosis, Behçet disease ....), infectious, vascular or hereditary (Leber's disease).

A diagnosis of multiple sclerosis had to be discussed, but it remained very atypical: the severity of optic neuropathy, purely ophtalmological tropism, and especially the absence characteristic hypersignals in white matter on cerebral MRI.

Devic disease (Neuro Myelitis Optica), associated with transverse myelitis. An acute optic neuritis in 72% of cases. the positivity of NMO antibodies (antibodies directed against aquaprin 4) is suggestive of neuromyelitis optica. However, the absence of NMO antibodies does not rule out the disease.

Progressive multifocal leukoencephalopathy is a severe myelinating disease of the central nervous system caused by reactivation of the poliomavirus JC, which affects immunosuppressed individuals. Asymptomatic seroconversion to the JC virus usually occurs in childhood.

Eighty to 90 percent of healthy adults are seropositive for JVC. The virus usually remains silence in the kidney cells or the lymph organs.

When the cellular immune response is deficient, it can be reactivated, spreding to the centtral nervous system by a hematogenous route and inducing lytic infection of oligodendrocytes. This disease was quite uncommon before 1984.In the early 1980s, the epidemiology of progressive multifocal leucoencephalopathy changed as AIDS became a major source of cellular immunosuppression. Eighty percent of patients have AIDS.

The presentation of Progressive multifocal leukoencephalopathy is usually multifocal with sub-acute neurological deficits including weakness (hemiparesis or monoparesis) confusion, appendicular or gait ataxia and visual symptoms (hemianopsia or diplopia).

However clinical manifestations vary depending on the distribution of the demyelinating lesions.

Another particularity of this case is the monofocal presentation. Repeating cranial MRI can help exclude other diagnoses.

The characteristics of MRI results in our patient’s lesion are quite typical, although progressive multifocal leukoencephalopathy lesions are usually multiple and asymmetric. The lesions are hypointense on T1 sequences and hyperintense on T2 sequences. The demyelinating process affects the subcortical white matter end U fibers.

In the past, the gold standard for the diagnosis of Progressive multifocal leukoencephalopathy was brain biopsy. Due to the risk of fatal complications and morbidity with the procedure, detection of JC virus DNA in the cerebrospinal fluid by 

PCR has now replaced brain biopsy for the diagnosis. PCR analysis has a sensitivity of 72 to 93 % and specificity of 92 to 100 %.


The diagnosis of optic neuritis was made, and the patient was hospitalized in the Ophthalmology Department for further exams and medical care. Intravenous steroids was immediately instaured 1 g day for 3 days and then 1mg/kg/day associated with adjuvant treatment.

Medical follow up

After 3 days the visual improved in both eyes, 1/20 in the right eye and 0,2/20 in the left eye.

An infectious examination doctor diagnosis on cerebral MRI imaging progressive multifocal leuco-encephalopathy. Blood test results were as follows: Antibodies against HIV was positive. Antibodies against hepatitis B virus and hepatitis C virus were all negative. Based on these results progressive multifocal leukoencephalopathy was diagnosed linked to immunosuppression secondary to Human Immunodeficiency Virus. We had immediately stopped corticosteroid therapy and we started antiretroviral therapy.


After 3 months of antiretroviral therapy, the visual recovery was total 20/20 (-3.00 d) in the right eye and 10/20 (-4.50 d) in the left eye. Fundus examination had normalized. No relapse occurred after a year follow-up. 

Although several drugs have been tested for Progressive multifocal leukoencephalopathy there is no approved treatment of this disease. Nevertheless, whenever possible cell immunity should be restored. Thus, highly active antiretroviral therapy improved survival in HIV patients with Progressive multifocal leukoencephalopathy.


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