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Primary Angiitis of the Central Nervous System: A Diagnostic Challenge

Primary angiitis of the central nervous system (PACNS) is a recurrent rare inflammatory disorder affecting the small and medium-sized vasculature of brain and the spinal cord and leptomeninges (Hajj-Ali, & Calabrese, 2013). PACNS is responsible for cerebrovascular events in 3 – 5% of patients under 50 years of age (Hajj-Ali, & Calabrese, 2014). It is believed to be caused by TH1 mediated release of inflammatory cytokines into the walls of the Central Nervous System (CNS) blood vessels leading to vascular destruction. However, current knowledge of the exact pathophysiology is limited and this has delayed advances in its diagnosis and treatment. Most often, diagnosis is based on a combination of clinical presentation, imaging (Magnetic Resonance Imaging (MRI), Magnetic Resonance Angiography (MRA)), brain biopsy and laboratory and Cerebral Spinal Fluid analysis (CSF) (Beuker et al., 2018). This paper presents two interesting cases of primary CNS vasculitis.

Case 1

A 46-year-old male patient with a history of hypertension presented to the Emergency room with severe headaches and right-sided blurry vision. Computed Tomography (CT) brain revealed intra-parenchymal hemorrhage on the left occipital region with intraventricular extension. ( see figure 1.). CT angiography did not reveal any obvious vasculitic process. On the first day of admission, the patient developed complete left oculomotor nerve palsy with worsening diplopia, left pupil measuring 5-6mm, altered mentation and progressive lethargy. A right-sided ventriculostomy drain was placed emergently and revealed an opening pressure of 35cmH2O. MRI of the brain showed diffuse patchy attenuations involving the cerebral hemispheres bilaterally and cerebellar hemispheres.  Figure 2. (1^st MRI) The patient was kept in neuro-intensive care unit with close monitoring, intubated and sedated. .  His neurological examination remained unchanged with a Glascow Coma Scale score of 5. At day 11, the patient received an infusion of Intra-Venous ImmunoGlobulin (IVIG) and Solumedrol for 9 days with no clinical improvement. IVIG was discontinued on day 20 and plasmapharesis initiated. A thorough workup for coagulation, rheumatologic, autoimmune and infectious (bacterial, fungal, viral) etiologies was negative. Suspicion remained high for PACNS and decision was made to reinitiate a second course of IVIG and steroids with gradual improvement starting from his distal extremities. He was successfully weaned off mechanical ventilation and was tolerating oral nutrition. Brain biopsy was discussed multiple times with patient’s family who opted for conservative management. Given patient’s neurological improvement with current management and risks associated with neurosurgical intervention, decision was made to monitor patient’s progress with serial MRI scans and frequent outpatient follow-ups. The patient was continued on prednisone 40mg PO daily and discharged to a rehabilitation facility. He showed remarkable improvement with this treatment and was able to ambulate with assistance during his rehabilitation.  Patient came for follow-up 3 months later fully ambulating and patient remain on 20 mg of prednisone daily.

CT scan of the head shows a hypedense lesion in the left occipital region with extension into the ventricles.

Initial MRI FLAIR imaging shows hyperintense lesions in the periventricular white matter area

Follow MRI of the brain FLAIR imaging shows areas of encephalomalacia in the periventricular our area.  Consistent with normal progression of the vasculitic lesions in the brain.

Case 2

            A 22-year-old Asian male with recent diagnosis of seizure disorder and reported encephalitis of unknown etiology four months prior to admission presented to the emergency department with recurrent generalized tonic-clonic seizures. He had prior complicated course of the disease requiring admission for intensive care due to suspected encephalitis. An MRI brain from pior admission showed areas of increased signal in the temporal and left basal ganglia region that enhance with contrast.  Patient had multiple studies done including CSF analysis that was negative for infection.  (figure 3).  Patient went to brain biopsies, both of which were inconclusive.. Thorough workup including coagulation screen, rheumatologic screen, autoimmune and infectious disease panels were all negative. On  this admission, the MRI brain showed areas of increased signal in the left temporal region and right frontotemporal regions.  The distribution was in the right MCA territory and ACA territoriesMRA showed no evidence of large vessel arterial or venous phase abnormalities. MRV showed no evidence of deep sinus thrombosis.  The patient was empirically started on Dexamethasone, Vancomycin, Cefepime, and Acyclovir. Cerebrospinal fluid (CSF) studies were non-diagnostic. His clinical condition improved on Dexamethasone and Levetiracetam with no changes on repeat imaging and antibiotics were then discontinued. Primary angiitis of the central nervous system was suspected and the decision was made to discharge the patient on hospital day 4 on prednisone 40mg PO daily and levetiracetam. The patient was neurologically stable, his cognition improved and repeat MRI showed no acute changes. The prednisone was, therefore, tapered off over a period of one month.  ( Asia come and see there is a lot more information, but basically patient was on steroids for about 4-5 months and we decided to decrease them and he has more seizures and worsening imaging. He is now chronically on steroids.)

Figure 3. White matter hyperintensities on magnetic resonance imaging

Discussion

            PACNS is a rare inflammatory vasculitide with a broad range of differential diagnoses, including primary inflammatory and infectious causes of vasculitis. Brain biopsy has traditionally been considered the gold standard for diagnosis of the disease. However, brain biopsy only reveals diagnostic histopathological abnormalities in only about 50% of the cases, with > 25% false negatives having associated risk factors (Torres, Loomis, Cucchiara, Smith, & Messé, 2016). Case 2 patient had two non-diagnostic brain biopsies. MRI scans have been found to have sensitivity of 90-100%, but with lower specificity (Boulouis et al., 2017). Due to the potentially harmful immune-suppressants used to treat PACNS, it is still beneficial to obtain brain biopsy if possible to confirm diagnosis. Brain biopsy may, however, not be possible in every case and a multi-disciplinary approach is required by numerous physicians to ponder the risks of obtaining a brain biopsy versus the risks of immunosuppressive therapy (Berlit, & Kraemer, 2014). There have been reports of MRI scans being utilized to assist in presumptive diagnosis of PACNS. Serial MRI scans of the brain and spine allow for close observation of the number, size and location of lesions during immunosuppressive therapy. If clinical suspicion for PACNS remains high after thorough workup and brain biopsy cannot be performed or is non-diagnostic, the use of steroids should be considered (Beuker et al., 2018).