Commentary case

By

Prof. Dr. : Fawzy Megahed

A 46-year-old woman developed progressive dyspnea over

a 2-month period.

The condition started 2 years ago when shedeveloped intermittent, dull, left-sided retro-orbital headaches. These were not associatedwith nausea, vomiting, photophobia, or flashlights, nor were severe enough to interrupther daily routine.

One month later, she suddenly lost vision in her left eye and was diagnosed with a retinal

detachment.

2 month later ,she started feeling dizzy anddeveloped an ataxic gait. She also appearedwithdrawn and had a decreased appetite,which her family attributed to the recentvisual loss .

3 months later , she had lost nearly 40pounds. She started having intermittentepisodes of hyperventilation that wouldresolve spontaneously.

However, these episodes became morefrequent and prolonged and she developedconfusion, drowsiness, and generalizedweakness. 5 months later , she was admittedfor continuous hyperventilation andrespiratory distress .

Arterial blood gas analysis revealed a severerespiratory alkalosis with a pH 7.56 and PCO29 mm Hg.

Review of systems revealed no history offever, infections, rashes, ulcers, myalgias,joint pain, or paresthesias. She denied anyexposure to toxins and reported no sickcontacts .

Examination

• She was a thin woman in mild distress from tachypnea with a respiratory rate of 30 breaths per minute

• Oxygen saturation was 100% on 2 liters nasal cannula.

• She was normotensive with a regularheart rate and rhythm.

• Her mouth was dry and no ulcers wereseen.

• There were no skin rashes.

Neurologic examination:-

• She was drowsy and oriented only to herselfbut followed simple commands.

• Speech was clear.

• Sensation was intact.

• Her right pupil was 3 mm and reactive to lightand her left pupil had post-surgical findings.

• Visual fields were normal in her right eye.She had no vision in her left eye.

• Eye movements were full, with slightlydecreased upgaze.

• Motor exam revealed a spastic tone in theright limbs compared to the left. There wasright arm and leg drift with 4/5 strength.Strength on the left was 4+/5.

• Muscle stretch reflexes were asymmetric,being 3+ in right arm and patella and 2+ inleft arm and patella.

• Clonus was present in both feet but more onthe right.

To summarize the case ………….

Our patient presented with a headacheand retinal detachment 1 month beforeshe developed neurological symptomsthat localized to the brainstem(dizziness and ataxia). As thesesymptoms worsened, she developedprogressive hyperventilation over a 2-month period.

What is yourdifferentialdiagnosis ?

• Multiple Sclerosis

• Sarcoidosis.

• Systemic Lupus Erythematosus.

• Sjögren’s Syndrome

• Primary CNS Vasculitis.

• Vogt-koyanagi-harada (VKH) Syndrome

• Cerebral Lymphoma

• Others

What should be the next step ?

Brain MRI showed extensive

hyperintense signal changes on FLAIR and T2-weighted images involving the supratentorialwhite matter, midbrain, pons, medulla,middle cerebellar peduncles, and part of thebasal ganglia and thalami.

There was no restriction of diffusion ondiffusion-weighted images. There waswidespread sulcal effacement and cisternaleffacement .

Intracranial MRA revealed

mild irregularity and stenosis of thesupraclinoid segments of both internalcarotid arteries and the A1 segment of theright anterior cerebral artery.

There was moderate stenosis of the inferiordivision of the right middle cerebral arteryand irregularity and mild fusiform dilatationof the distal M2 segment.

• There was also mild stenosis of the superiordivision of the left middle cerebral artery andirregularity in the M2 segment .

• MRI of the cervical spinal cord was

normal.

•WHAT ARE THE NEXT INVESTIGATIONS?

Serology was negative for ANA, Anti SSB, antiSSA, Anti JO, Anti centromere, Anti ds DNA,Anti ribosomal, Anti smith, and Anti SM/RNPantibodies. ANCA / MPO / PR3 testing wasnegative.

• Serology was negative for HIV, HTLV, HSV, JCvirus and a paraneoplastic work-up wasnegative.

• Testing for skin pathergy was negative

•CSF analysis showed lymphocytic

pleocytosis and an elevated proteinconcentration of 52 mg/dL.

• Testing for oligoclonal bands, myelin

basic protein, and IgG index were positive.

What is yourdifferentialdiagnosis ?

What is the next step ?

Brain biopsy

Brain biopsy of the right frontal lobe

demonstrated necrosis and perivascularinflammation of multiple venules infiltratedpredominantly by lymphocytic inflammatorycells

Perivenous demyelination was not identified(confirmed by Luxol Fast Blue and CD68immunostaining) .

Neither arteritis nor encephalitis wasidentified.

To summarize the case ………….

Our patient presented with a headacheand retinal detachment 1 month beforeshe developed neurological symptomsthat localized to the brainstem(dizziness and ataxia). As thesesymptoms worsened, she developedprogressive hyperventilation over a 2-month period.

Brain MRI showed extensive increased signalon FLAIR and T2-weighted images, mainlyaffecting the white matter bilaterally but alsoin the basal ganglia and thalami, andsymmetrically extending from the cerebralhemispheres down to the brainstem andeventually into the upper cervical spinal cord.

• Intracranial MRA showed several areas ofmild irregularity and stenosis suggestive ofcerebral vasculitis.

• Brain biopsy, however, revealed venulitis andnecrosis with no evidence of arteritis ordemyelination .

Thus, the clinical, radiological, andpathological findings were most consistentwith …………………………..

Neuro-Behcet’s disease

The patient was treated withmethylprednisolone 1000 mg IV once dailyfor 5 days followed by prednisone 60 mgorally once daily.

During this period, an ulceration in thevermillion border of the patient’s left upperlip was noted

After beginning corticosteroids there wasremarkable improvement in her mentalstatus and hyperventilation and she wasdischarged to a rehabilitation facility.

Further work-up revealed that she harbors

the HLA-B51 allele.

DiscussionBehcet’s disease is common in the MiddleEast, with an incidence of 0.58 per 100 000population and a prevalence in Turkey of 420per 100 000 population. In the Westernhemisphere the exact incidence is less certainbut is estimated to be 0.24 per 100 000population and with a prevalence between0.12 and 7.5 per 100 000 population .

The onset usually occurs in the third decadeof life with an equal sex predilection(although a male preponderance in Turkeyhas been described) .

Central to the pathogenesis of Behcet’sdisease is an autoimmune vasculitis possiblyinduced by microbial pathogens in geneticallysusceptible individuals such as those with theHLA-B51 gene .

Increased expression of severalproinflammatory cytokines seems to beresponsible for the enhanced inflammatoryreaction in patients with Behcet’s.Specifically, high serum levels of IL-6 and IL-8have been found during active phases of thedisease .

Polymorphisms in the promoter region of thetumor necrosis factor gene (located in thevicinity of the HLA-B locus) and in theendothelial nitric oxide synthase gene arealso thought to play a role . While bloodvessels of all sizes can be involved, thedisease tends to mainly involve small veins.

Clinically, patients typically present withrecurrent mouth ulcers that can be severe,involving the soft palate and oropharynx andcausing difficulty eating, swallowing, andspeaking .

Genital ulceration is the second mostcommon manifestation of Behcet’s disease,developing in over half of patients .

Ocular disease is seen in 30–70% of patientsand usually begins after the mouth ulcers,but in 20% of patients these may be thepresenting feature .

The most common ocular finding isinflammation of the anterior uvea and thevascular middle layer of the eye. In additionto anterior uveitis, patients can present witha broad range of ophthalmologic conditions,including posterior uveitis (chorioretinitis),retinal vasculitis, and retinal detachment .

Neurological manifestations, when theyoccur, tend to develop late, with averagetime between onset of the disease andneurological symptoms of about 6 years .

In neuro-Behcet’s disease there typically isdirect involvement of the brain, usually in theform of a meningoencephalitis with anintense inflammatory infiltration oflymphocytes, eosinophils, and macrophages,and areas of necrosis and apoptotic neuronalloss .

In the non-parenchymal form, vascularcomplications involving thrombosis withinlarge veins and occasionally arteries occur, aswell as vasculitis that more often involvessmall veins . In some cases, an obliterativeendarteritis of the vasa nervorum can resultin focal vascular dilatation and aneurysmformation .

The structures within the brainstem,thalamus, basal ganglia, and white matter areall affected to varying degrees. In chroniccases, there can be striking atrophy ofbrainstem structures seen on MRI . Thisexplains why patients often developbrainstem syndromes, hemiparesis, andataxia .

Headache is also common, both migraine andtension type . The course may be relapsing-remitting initially followed by a secondaryprogressive phase, and occasionally aprimary progressive course is seen from thebeginning .

Our case nevertheless is remarkable inseveral ways.

First, almost all patients with Behcet’sdisease develop recurrent oral ulcerations. Soconsistent is this finding that it is aprerequisite for the diagnosis according tothe International Criteria for Behcet’s Disease. Our patient did have an oral ulceration, butthis came very late in the course and onlyafter her other neurological symptomsappeared.

Second, our patient did not have anyevidence of genital ulcerations, skin lesionsor skin pathergy, or a hyper-reactivity to non-specific physical insults such as a pinprick.Each of these findings generally occurs in 50–60% of patients, although pathergy may beless frequent in patients from the Westernhemisphere .

Third, uveitis is the most frequent ocularmanifestation of Behcet’s disease. Whileretinal detachment has been well described,it is certainly uncommon.

Fourth, neuro-Behcet’s disease is rare,occurring in 10–20% of patients with Behcet’sdisease. Typically this develops several yearsafter the diagnosis of Behcet’s. To have apatient present with neurological symptomsis very rare.

Fifth, the most common presentation ofneuro-Behcet’s disease ismeningoencephalitis followed by venousthrombosis. While venulitis is typical forBehcet’s disease, it is still uncommon.

Sixth and finally, symptoms attributable tobrainstem involvement have been wellreported in patients with Behcet’s disease.

A Case of Neuro-Behcet’s Disease Presenting With

Central Neurogenic Hyperventilation

Behcet disaese

New international criteria (new ICBD)(London 2010)

Oral aphthae 2

Skin lesions (PF, EN) 1

Vascular lesions 1

Genital aphthae 2

Eye lesions 2

CNS lesions 1

Pathergy test 1

>= 4 score: sensitivity: 94%, specificity: 90.5%

Frequency of Clinical Manifestations of Behçet Disease

Feature Frequency (%)

Oral Lesions 100

Genital Lesions 75

Skin Lesions 60-90

Ocular Manifestations 50

Arthritis 50

Gastrointestinal Lesions 25

Thrombophlebitis 20

Central Nervous System 10-20

Epididymitis 5

Consensus classification of neuro-Behcet’s disease

• Parenchymal

• Multifocal/diffuse

• Brainstem

• Spinal cord

• Cerebral

• Asymptomatic (silent)

• Optic neuropathy

• Non-parenchymal

• Cerebral venous thrombosis: intracranial hypertension

• Intracranial aneurysm

• Cervical extracranial aneurysm/dissection

• Acute meningeal syndrome

• Peripheral nervous system (relation to BD uncertain)

• Peripheral neuropathy and mononeuritismultiplex

• Myopathy and myositis

Mixed parenchymal and non-parenchymaldisease

International consensus recommendation (ICR) criteria for NBD diagnosis(2014)

Definite NBD meeting all of the following three criteria

1. Satisfy the ISGa criteria for BD2. Neurological syndromeb (with objective neurological signs) recognised to be caused by BD and supported by relevant and characteristiccabnormalities seen on either or both:a. Neuroimagingb. CSF3. No better explanation for the neurological findings

Probable NBD meeting one of the following two criteria in

the absence of a better explanation for the neurological findings:1. Neurological syndrome as in definite NBD, with systemic BD features but not satisfying the ISG criteria2. A non-characteristic neurological syndrome occurring in the context of ISG criteria-supported BD

A -ISG International Study Group Criteria 1990 or any other accepted current or future criteriaB- The recognised syndromes and the ^characteristic findings on investigations are described in Table 4 and in the text

Primary neurological involvement (neurological

involvement directly related to BS)

Headache (migraine-like, non-structural)

Cerebral venous sinus thrombosis (extra-axial NBS)

Central nervous system involvement (intra-axial NBS)

Neuro-psycho-Behçet's syndrome

Peripheral nervous system involvement

Subclinical NBS

• Secondary neurological involvement

(neurological involvement

• indirectly related to BS)• Depression and headache

• Neurological complications secondary to systemic

involvement of BS (i.e., cerebral emboli from

cardiac complications of BS,

• Increased intracranial pressure secondary to

superior vena cava syndrome)

Neurologic complications related to BS

treatments (i.e., CNSneurotoxicity with cyclosporine;

peripheral neuropathy secondary to thalidomide or

colchicine)

Coincidental – unrelated (non-BS) neurological

involvement

Primary headaches and any other coincidental

neurological problem