Primary angiitis of CNS : neuropathological study of three autopsied cases with brief review of literature.
Primary angiitis of CNS(PACNS) or granulomatous angiitis of CNS is a rare inflammatory disease of small blood vessels mostly confined to the CNS. The clinical and pathological features of 3 autopsied cases are described. Clinically all the three PACNS patients were young males, age ranging from 19 to 31 years. All presented with varied neurological manifestations. There was no evidence of systemic disease in any of the cases. The ESR was normal and CSF analysis showed chronic meningitic pattern. The cerebral angiogram in one case was normal and the CT scan done in another case showed multiple intracerebral haematoma due to vasculitis. Brain biopsy was not done. Diagnosis was made at post-mortem examination. Histology showed characteristic but variable degree of granulomatous and non-granulomatous angiitis of small vessels. Venulitis with parenchymal haemorrhages was the predominant feature and in one case phlebitis with thrombosis was noted. Since the disease responds to steroids and immunosuppressive therapy, establishing antemortem diagnosis is important. In view of the association of angiitis of CNS with bacteria and viral infections, their role in the evolution of the disease needs to be investigated.
Primary angiitis of the central nervous system (PACNS) is an uncommon, idiopathic, recurrent form of small vessel vasculitis, occasionally involving medium sized vessels. The disorder is largely restricted to the CNS, involving the cerebral hemispheres, cerebellum, brain stem or spinal cord and roots, and not causally related to immune mediated generalized systemic vasculitides. Most cases have a fatal outcome and tissue diagnosis has rarely been established. In view of the fact that some cases respond well to steroids and immunosuppressive therapy,, with prolonged remission, it is important to recognize these cases. However, varied and protean clinical manifestations and nonspecific angiographic features, makes the antemortem diagnosis difficult. We report three autopsy proven cases of PACNS, with a brief review of literature.
Case 1: A 31 year old man, chronic smoker, presented to the neurological services with history of episodic headache and unconsciousness of two months duration. Three months earlier he had suffered from intermittent fever, and one episode of right sided facial weakness. He was confined to bed since one and a half months with a deteriorating level of consciousness. On examination he was in altered sensorium, disoriented, apathetic and had poor comprehension. He had bilateral early papilloedema and receptive dysphasia. Frontal release signs were present. Patient had no obvious motor deficit, except increased tone in all the limbs. He was responding to pain all over the body, however detailed sensory examination could not be carried out.
The routine haematological and biochemical investigations were unremarkable. The ESR was 8 mm/hour (Westergren). Lumbar CSF was clear with 100cells/mm3 (all lymphocytes), protein 235mg%, glucose 20mg%. Serum and CSF VDRL was nonreactive. Blood and CSF cultures were sterile. Cerebral angiogram was normal. Cranial CT scan was not done. Provisional clinical diagnosis was benign intracranial hypertension. Gradually the patient developed florid papilloedema and pyramidal signs. He worsened in the level of sensorium and expired after [eight] days of hospital stay inspite of antioedema and other supportive therapy.
Case 2: A 18 year old male suffering from generalized convulsions for the past 4 years was admitted to the hospital for treatment of generalized cluster attacks. He received antiepileptic therapy with poor compliance. Details of treatment received were not available. On examination he was deeply comatose and in a state of shock with hypotension, and generalized hypotonia of all limbs. Further examination was not possible. A provisional clinical diagnosis of status epilepticus was made. He could not be revived and died after 6 hrs. Lumbar CSF collected at autopsy revealed 40 cells/mm3 (all lymphocytes), protein 140mg%, and 2000 RBCs/mm3.
Case 3: A 31 year old man was admitted in the Neurology ward four times over a period of two years. During the first admission he presented with episodic headache of two years duration and recurrent attacks of right hemiparesis, each lasting for 5-7 minutes. On examination, he had right sided hemiplegia and right hemianaesthesia and early papilloedema. At that time a cranial CT scan had revealed a left fronto-parietal hyperdense lesion with minimal enhancement on contrast and perilesional oedema. The clinicoradiological diagnoses considered were haemorrhagic infarct, arterio-venous malformation with haemorrhage or a granulomatous lesion. He was treated with aspirin and pentoxyphylline. He recovered completely from the symptoms and was discharged after 21 days of hospital stay. He was however readmitted after a month with another episode of right hemiparesis. A repeat cranial CT scan revealed the old lesion and another fresh haemorrhagic lesion in the territory supplied by the posterior division of left middle cerebral artery, separate from the earlier lesion.
Examination of lumbar CSF revealed 110 cells/mm3 (98% lymphocytes), protein 97mg% and sugar 40mg%. Antimycobacterial antibody, lgG type and mycobacterial immune-complexes were detected in CSF. CSF Herpes zoster lgG antibody titres done on two occasions within an interval of two and a half months were 29 AIU/ml and 100 AIU/ml respectively indicating a rising titre of the antibody. CSF and serum VDRL were non-reactive. ESR was 10mm/hr (Westergren), the rest of the haematological and biochemical parameters were within normal limits. Vasculitis work-up and urine for homocystinuria were negative, serum lactate was normal. A clinical diagnosis of tuberculous meningitis with arteritis was considered, and the patient received antituberculous drugs with steroids. Initially he showed clinical improvement, however he discontinued the treatment after 5 months. A year later he was admitted to the hospital for the third time for the recurrence of right hemiparesis and additional right motor seizure with generalization. He again received antituberculous therapy and phenobarbitone to control seizures. Repeat CSF examination during this admission revealed 60 cells/mm3 (all lymphocytes), protein 84mg%, sugar 51 mg%, antimycobacterial antibody persisted in CSF. CT scan revealed bilateral white matter hypodensities suggestive of bilateral white matter oedema probably due to vasculitis, and the earlier lesions had resolved. It was decided to further investigate the patient electively, but he was discharged on request. Unfortunately, a week later he presented with acute onset of altered sensorium and vomiting. He lapsed into coma rapidly and expired the same day.
A complete autopsy was performed in case 2, while in cases 1 and 3 partial autopsy, limited to removal of the brain alone, was conducted. Representative sections from different areas of formalin fixed brain and parenchymatous organs in case 2, were processed for paraffin sectioning. These were routinely stained with haematoxylin and eosin, PTAH for glial fibres, luxol fast blue for myelin and Verhoff-van Geison (VVG) for elastic tissue. Special stains used to identify mycobacteria and fungi included Ziehl-Niehlson's stain and Gomori's methanamine silver (GMS) respectively.
Gross: In all the three cases, the brain was diffusely oedematous and congested. The leptomeninges were opaque. No mass lesions could be felt. The larger vessels of circle of Willis were grossly normal. In the third case, thrombosis of superficial cortical veins was evident, without any underlying infarct. Thin blood clots were seen emerging out of the brain parenchyma. Serial coronal sections of cerebral hemispheres in case 1 revealed a large haematoma in the right parietal white matter extending medially to involve the head of the caudate nucleus, anterior limb of internal capsule and the thalamus. In the second case, multiple smaller parenchymal haematomas were observed in the left frontoparietal white matter, basal ganglia and hippocampus. In the third case, in addition to old healed haemorrhagic left fronto-parietal lesion, another large fresh intracerebral haematoma in right fronto-parietal white matter involving basal ganglia, internal capsule and thalamus rupturing into ventricle and extending into sub-arachnoid space was seen [Figure - 1]. In all the three cases multiple petechial and linear streaks of haemorrhages were also seen diffusely in cerebral hemispheres, brain stem and cerebellum, involving both grey and white matter. Examination of the parenchymatous organs in case 2 revealed terminal congestion of visceral organs, and pulmonary oedema. Luminal and adventitial aspects of all the major vessels were normal.
In case 1, diffuse small vessel vasculitis involving arteries, arterioles, capillaries and venules were seen in the leptomeninges and brain parenchyma. Serial sections revealed the vasculitis to be anatomically focal and segmental and morphologically both granulomatous and non-granulomatous (lymphomononuclear or transmural necrotizing) in nature. There was predominance of granulomatous vasculitis with occasional Langhan's type giant cell [Figure. 2a]. Occasional vessel showed luminal occlusion by thrombosis. Perivascular oedema and plump reactive astrocytosis were seen. Surrounding parenchyma revealed variable degree of ischaemic changes and haemorrhages.
In case 2, as well, both granulomatous and non granulomatous lymphomononuclear angiitis was seen in the leptomeningeal vessels and brain parenchymatous vessels, the granulomatous form being predominating. Many foreign body and Langhan type giant cells were seen in the granulomas. The varied vascular lesions were frank transmural fibrinoid necrosis [Figure. 2b], thrombosis, organisation and recanalisation of the thrombi and endarteritic changes in small muscular arteries, indicating the chronic progression and temporal evolution of lesions. Some of the perivascular zones revealed glial scars, neovascularisation and geographic patterned spongy ischaemic areas, representing the secondary effects of vasculitis. The brain parenchyma away from vasculitis revealed diffuse oedema, significant reactive astrocytosis, ischaemic changes and focal haemorrhages. The diffuse distribution and variable vascular and parenchymal lesions corresponded to the long duration of the disease process.
In case 3, the patient had recurrent episodes over two years. Microscopic examination of the sections from the brain revealed essentially non granulomatous lymphomononuclear vasculitis of both arteries and veins [Figure. 2c], while an occasional vessel had transmural granulomatous reaction with giant cells. Fibrin thrombi were seen in some of the small parenchymal arteries and occasional superficial cortical veins with surrounding oedema, focal haemorrhages and reactive gliosis. In addition, a large resolving haematoma with rarefaction of surrounding parenchyma and haemosiderin laden macrophages was seen. No vessel could be identified in the haematoma. Rarely, transmural fibrinoid necrosis and vascular fibrosis were found in different areas, indicating the acute and chronic lesions in evolution. Special stains for acid fast bacilli and fungi were negative. A diagnosis of PACNS was made in all the cases. Various extracranial and parenchymal vessels in visceral organs in case 2 were essentially normal with no evidence of vasculitis. Circle of Willis was not involved by vasculitis in all the cases. There was no microscopic evidence of viral encephalitis in case 3, where rising titres of Herpes zoster antibody (IgG type) were noted.
PACNS was probably first described by Harbitz in 1922 as 'an unknown form of angiitis'. This obscure condition was rediscovered 30 years later by Newman and Wolf as 'non-infectious granulomatous angiitis involving CNS and was subsequently delineated as a distinct clinico-pathological entity by Cravioto and Feign. Two cases were reported earlier from India.,
PACNS affects blood vessels in any part of CNS with a diameter of 200µ m and below. Rarely, larger vessels are involved. The pathological features in the present cases were characteristic of granulomatous angiitis of CNS associated with lymphomononuclear perivasculitis and focal fibrinoid necrosis of the vessel wall, involving both arteriolar and venular components, but relatively sparing the large and medium sized muscular arteries, resulting in multiple haemorrhages in the brain. The descriptive term 'granulomatous angiitis' - first introduced by Cravioto and Feign remains a popular synonym even though fewer than 50% of PACNS cases are histologically granulomatous. Occasionally the disease may affect predominantly veins and venules, as we noticed here. lschaemic lesions, though described, were less frequent in these cases., The angiitis in our cases was focal and segmental as reported earlier.,
Rarely, clinically silent lesions have been seen in visceral organs at postmortem examination., However, we did not observe systemic vasculitis in the case 2 where a complete autopsy was performed.
Clinically most PACNS patients are young or middle aged (mean age 45 years, range 3-96 years), men outnumbering women. Most common presenting complaints include headache, weakness, confusion, multi focal neurologic deficits and psychiatric disorders. In the reported cases, diverse clinical manifestations include diffuse encephalopathy, myelopathy, chronic meningitis, cranial nerve palsies (which tend to occur late in the course of the disease), stroke, seizures, ventriculitis, mass lesion mimicking tumour and occasionally radiculopathies. Our cases presented with features of benign intracranial hypertension (case 1), seizure disorder (case 2), chronic meningitis with arteritis and recurrent stroke like episodes (in case 3). Deaths in all the three cases were the direct result of PACNS, occurring between 3 months to 4 years after the onset of symptoms.
There are no definite diagnostic laboratory tests for PACNS. However, in contrast to giant cell arteritis (GCA) with systemic involvement, the ESR generally is mildly elevated at the most and CSF values reflect a chronic meningitic pattern. Cerebral angiography findings are non-specific, and not always diagnostic. The angiographic findings in some drug abusers may mimic PACNS., However, in our cases there was no history of drug abuse and pathologic features of drug induced vasculitis such as multisystem medium sized muscular artery involvement with predilection to branch points, sparing of veins and absence of giant cell, were conspicuously absent. It is reported that approximately one quarter of biopsy proven PACNS showed normal angiographic study, while 50% showed non-specific arterial narrowing and only 25% demonstrated classical segmental narrowing or beading. We did not find any angiographic abnormality in our first case. CT abnormalities are also non specific. High density lesions due to intracerebral haemorrhage, low density ischaemic lesions, or normal scans were described in many cases. In case 3, CT showed multiple intracerebral haematomas and bilateral white matter oedema due to vasculitis. Recent studies have shown that the diagnosis may be supported by contrast enhanced MRI findings of a hypointense granuloma surrounding a hyperintense blood vessel.
Brain biopsy has been advocated to establish diagnosis when angiogram is negative. Although it remains the most specific diagnostic procedure for vasculitis, it can be negative due to patchy nature of the disease. The recommended biopsy site is the nondominant hemisphere, usually the temporal lobe, including an area with a longitudinally oriented surface meningeal vessels.
The aetiology of PACNS remains speculative. The most note-worthy clinical association of PACNS is the past or current infection by H. Zoster and Hodgkin's diseases.,, Other viruses such as CMV and HTLV-III have also been implicated. A cerebral vasculitis apparently similar to PACNS has been produced experimentally with Mycoplasma gallisepticum and mycoplasma like organisms were found in the walls of the affected cerebral arteries. Two autopsy cases of PACNS were also reported to have mycoplasma like inclusion bodies in the giant cells under electron microscope, but cultures of the frozen brain tissue for mycoplasma were negative.
The major differential diagnosis for PACNS include systemic vasculitis, sarcoidosis, temporal arteritis (GCA), Takayasu's disease, lymphomatoid granulomatosis and other infectious angiitis including herpetic angiitis. It is readily distinguished from systemic necrotising vasculitis like polyarteritis nodosa, where necrotising lesions involve medium sized and small arteries with frequent distal spread into arteriole, but veins and capillaries are usually spared. Neurosarcoidosis can be excluded in the absence of evidence of systemic disease and in the presence of necrotizing vasculitis separate from granulomatous lesions and absence of parenchymas granulomas as seen in the present cases. The herpetic angiitis, either granulomatous or nongranulomatous, occurring as part of the syndrome of ophthalmic zoster and contralateral hemiplegia or as generalised CNS involvement in the immunosuppressed, is proposed to be by direct viral invasion of blood vessels., The significance of antimycobacterial antibody and immune complexes and the rising titres of Herpes zoster lgG antibody in CSF in case 3 is not clear. Some authors consider PACNS to be a variant of GCA., However, PACNS is generally considered distinct from intracranial involvement of GCA as anatomically the lesions of GCA involve larger arteries and veins and are not characterized by prominent granulomatous response., In the present cases diffuse vasculitis in leptomeninges and parenchyma with sparing of large arteries of circle of Willis and variable ischaemic changes and haemorrhages in brain parenchyma were seen, which is known to be characteristic of PACNS. The observed pathological changes correlated with the duration of neurological symptoms. Detailed studies of vessel immuno reactivity, as done for systemic vasculitis, including immunofluorescence studies for detection of antibodies or immune complexes have been non-contributory. Pathomorphologic appearance suggests a disorder of cell-mediated immunity, probably secondary to a viral infection. lmmunosuppression and altered cellular immunity (CD4 T cell mediated) may play a major role in the aetiology and evolution of PACNS. Absence of specific clinical features and appropriate investigative modalities, short of brain biopsy, have made the diagnosis of PACNS difficult till date.