J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.2.156 on 1 February 1981. Downloaded from

Journal of Neurology, Neurosurgery, and Psychiatry, 1981, 44, 156-160

Short report CNS involvement in malignant atrophic papulosis (Kohlmeier-Degos disease): vasculopathy and

DARAB K DASTUR,* B S SINGHAL,t AND H J SHROFFT From the Neuropathology Unit,* the Department of Neurology,t and the Department of Dermatology,$ Grant Medical College and J J Group of Hospitals, Bombay

SUMMARY The clinical features in a 42 year old man with malignant atrophic papulosis with CNS involvement are described. They included mental dysfunction, paraesthesiae, weakness of left limbs, with pyramidal tract signs, bilateral ptosis, progressing to total ophthalmoplegia and obtundation. There were two crops of characteristic papular on trunk and limbs, with ter- guest. Protected by copyright. minal evidence of a coagulopathy and bruises, resulting in death in six months. Papular revealed multiple microinfarcts in the dermal collagen. The brain showed multiple small haemor- rhagic infarcts of both hemispheres, the lower mid-brain, pons and a cerebellar peduncle. Microscopy showed fibrin exudation in the leptomeninges, various stages of of small without inflammatory reaction, and corresponding acute and subacute microinfarcts. The pathogenetic basis of the disease appeared to be a combined vasculopathy and coagulopathy.

Kohlmeier' and Degos et al2 almost simultane- associated malabsorption and renal lesions), ously described a rare and potentially fatal Vanderhaegen et a19 (with many motor cranial papulosis of the skin, with occlusive changes in nerves involved). Hall-Smith'0 (describing a the small arteries as the basic . Subsequently diseasein a mother and son, Horner," and Degos et a13 described the condition as the "syn- McFarland et al12 (witlh perivascular infiltrates drome cutaneo-intestinal mortel," because the similar to those seen in other viral encepha- majority of patients died of multiple infarcts of lopathies). To this may be added a tenth case by the small intestine. Over the course of the past Basset et al.13 A comprehensive account of the three decades about 100 cases have been described cutaneous symptoms, the intestinal disorder, the from different parts of the world. neuro-occular manifestations, the basic pathology http://jnnp.bmj.com/ Of greater interest are the unusual cases where and pathogenetic considerations, has been pre- the characteristic malignant atrophic papulosis of sented by Degos and Kalis.14 Generally when the the skin is accompanied by widespread occlusive CNS lesions are present the intestinal lesions are vasculopathy of the brain and spinal cord with absent or mild. consequent multiple infarcts. The first to describe We report here probably the eleventh recorded such a combined disorder were Nomland and neuropathologically studied case of Kohlmier- Layton5 who also reported vascular lesions in the Degos disease, stressing the possible combined and . The subsequent cases were pathogenetic mechanisms of coagulopathy and on September 26, 2021 by those of Gever et ala and Culicchia et a17 (the same vasculopathy. case), Winkleman et a18 (two cases with detailed neuropathology), Strole et a14 (a patient with Case report Address for reprint tequests: Dr DK Dastur, Neuropathology Unit, Sir JJ Group of Hospitals, Bombay-8, India. Clinical features SBR, a man aged 42 years, a Accepted 25 September 1980 postal clerk, was first seen on 22 July 1970. In 156 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.2.156 on 1 February 1981. Downloaded from

CNS involvement in malignant atrophic papulosis (Kohlmeier-Degos disease) 157 January 1970, he had noted a few papules over reacted sluggishly to light. On 26 August, he had the body. In March 1970 he became forgetful. On hiccups and became semiconscious. The doll's eye 8 July 1970, he complained of left sided paraes- manoeuvre only elicited abduction of the right thesiae and developed an acute left hemiparesis. eye. On 5 September, he only responded to pain In 1958, he had been treated for pulmonary by extending the limbs. Three days before his death tuberculosis. on 12 September 1970, he had and Examination on admission showed papules with ulceration of left pinna, bruises and haematomas central umblication over the upper extremities, over the pressure sites of the scalp and back. chest and abdomen (fig IA). Neurological ex- There were no abdominal signs at any stage. amination showed impairment of memory for The clinical picture in this patient with skin recent events, mild blurring of disc margins, lesions and neurological involvement suggested dysartfiria, left hemiparesis with extensor left Kohlmeier-Degos Disease. plantar and impairment of pain sensibility on left Examination Clinical pathology The blood leucocyte (total WBC) side. was otherwise normal. Blood count was 9 6X 109/l, with neutrophil polymorphs pressure was 146/90 mmHg. He continued to 62%, eosinophils 8%, lymphocytes 24% and mono- deteriorate. He devloped retention of urine and by cytes 6%. The erythrocyte sedimentation rate was August he had bilateral pyramidal signs with 20 mm at the end of one hour (Westergren method). brisk tendon jerks and bilateral extensor plantar The urine was normal. Fasting blood sugar level was responses. Later he showed signs suggesting brain 4'99 and post-prandial 5 38 mmol/l. The VDRL was stem involvement: nystagmus on looking to the negative. Serum protein concentration was 68 g/l, right, bilateral ptosis (left more than right), the with albumin 29-6 g/l, alpha 1 globulin 2-2 g/l, alpha left pupil became larger than the right and 2 globulin 112 g/l, beta globulin 10 4 g/l and gamma guest. Protected by copyright. globulin 14-6 g/l. Serum alkaline phosphatase was 0,5 King-Armstrong Units, glutamate-oxaloacetate transaminase 0-65 g/l and glutamate-pyruvate trans- aminase M70 g/l. The ECG was normal. EEG showed abnormalities on the right side. Chest and skull radio- graphs showed no abnormality. Right carotid angio- gram and an air encephalogram were normal. Routine examination of cerebro-spinal fluid (CSF) on three occasions showed marked elevation of protein (be- tween 1-60 and 2-16 g/l) and of cells up to IXIOG/I (lymphocytes only). Lange's Colloidal Gold Curve was normal (all zeros). The blood erythropoietic and coagulation factors on two occasions are shown in the table. Pathology The main gross neuropathological findings were localised thrombosis of the superior sagittal sinus, the presence of multiple small surface and sub- A~~~~~~ surface haemorrhagic infarcts of both cerebral hemi- spheres, right more than left, haemorrhagic softening of the lower mid-brain and pons and haemorrhage in a cerebellar peduncle. Microscopic examination http://jnnp.bmj.com/ showed all possible stages of thrombosis of the arteries with extensive intravascular and extravascular de- position of fibrin in the superolateral and sulcal men- inges, accompanied by corresponding stages of infarc- . . S: .N ...... : : tion, mainly in the cerebral cortex; and thrombosis .... of some of the parenchymal vessels of the brain stem associated with acute softening and microhaemor- rhages. The changes in the other organs included small Fig 1 (A) Abdomninal sk n of the patient (umbilicus areas of pallor and disappearance of collagen in one on September 26, 2021 by at top right) showing papules, one of which (at lower of the skin papules, with a mild mononuclear cell left) is umbilicated. (B) One of the several small reaction representing micro-infarction, small haemor- infarcts in the skin showing pale area of broken down rhages in the stomach and kidney and severe acute- collagen (surrounded by better preserved collagen subacute inflammatory reaction in and bladder. bundles), including five small blood vessels, some The essential pathological features are illustrated in thickened, and a few scattered small mononuclear figs 1B, 2A and B, 3A, B, and C, and brief descriptions cells. (6) Haematoxylin and eosin X 175. are given in the legends. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.2.156 on 1 February 1981. Downloaded from

158 Darab K Dastur, B S Singhal, and H J Shroff guest. Protected by copyright.

Fig 2 (A) Coronal slice through cerebral hemispheres at the level of the posterior part of http://jnnp.bmj.com/ frontal lobes and anterior part of temporal lobes showing small haemorrhagic areas in the superolateral gyri, the right insular cortex, in both sub-thalamic and sub-pallidal regions and in the medial tips of the temporal lobes. The right hemisphere is appreciably Fig 3 (A) Thickened frontal leptomeninges showing smaller than the left. (B) Sections through three two thrombosed vessels (split arrow) (diameter of levels of the pons, the one at the upper left being larger vessel= 125 tm), and pale or dark masses of through the ponto-mesencephalic junction, showing fibrin. (B) Parietal leptomeninges showing early haemorrhage on both sides, with the larger one on fibrin- in (diameter= 630 rm) at top on September 26, 2021 by the right extending into the middle cerebellar left, normal patent in the middle, and infarcted peduncle (lower slice). cortex at lower right. (C) Dense fibrin thrombus totally blocking small meningeal artery (diameter= 205 ,tm); mild astrocytic reaction in cortical surface. (A) H & E X32; (B) H & E X63; (C) PTAH X160. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.2.156 on 1 February 1981. Downloaded from

CNS involvement in malignant atrophic papulosis (Kohlmeier-Degos disease) 159 Table Erythropoietic and coagulation factors

Blood sample of 17 August 1970 10 September 1970

Haemoglobin 15 5 g/dl 10 5 g/dl RBC (PCV) 5 Ox 1012/1 (0 45) 4-0 x 1012/1 (0 37) Platelets 125 x 109/l 93 x 109/1 Plasma prothrombin time Pt 13 min, control 12 min Pt 21 min. control 12 min Serum prothrombin time Pt 39 min, control 42 min Pt 40 min, control 41 min Activated PTT* - Pt 48 min, control 34 min Bleeding and clotting times 147 s and 310 s Clot retraction 20 % of serum (good) *PTT=Partial thromboplastin time Pt=Patient.

Discussion brain of and peri-vasculitis with small mononuclear cells. As this viral infection was a McFarland et al'2 reviewed the main clinico- year or more prior to the onset of papulosis, the pathological features of nine cases of this disease terminal vasculopathy was believed to be an im- with neurological involvement. They ranged in age munological reaction. Degos and Kalis14 suggest from three months to 55 years, seven being be- that their own of tween discovery antiarterial anti- the ages of 16 and 47 years, with a duration bodies provided evidence of an autoimmune of symptoms of one to six years. Hemiparesis or mechanism. hemiplegia, focal , facial paresis, inco- It is of interest that atrophic lesions closely ordination, dysarthria and hiccups, were the more resembling malignant atrophic papulosis were guest. Protected by copyright. common CNS signs; with multiple cerebral in- observed in SLE by Black and Hudson.16 It is farcts, with or without haemorrhagic changes and generally conceded,4 8 12 however, that the similar changes in the cerebellum or spinal cord, vasculopathy in malignant atrophic papulosis is dif- constituting the neuropathological findings. There ferent from that in was fair SLE, where both arteries and clinicopathological correlation at different are involved and the kidney is the site of stages of the neurological manifestation in our from that in patient. Thus, predilection; peri- nodosa, for instance, the left limbs were where it is more widespread and has florid in- more severely affected than the right, and the flammatory reaction; and from that in thrombo- infarcts in the right cerebral hemisphere were obliterans more angiitis where again is prominent than those in the left, and the prominent, skin lesions do not occcr and right frontal lobe was smaller. terminal The occular and parts of extremities are involved preferentially. brain stem signs were readily explained by the One other rare gross form of vasculopathy, namely and microscopic, haemorrhagic and Eales' disease with CNS 18 ischaemic lesions in the pons. involvement,17 differs from malignant atrophic papulosis in being a The mechanism of production of the vascular lesions which more proliferative disorder, with veins involved produced the small multiple infarcts but with a of the brain, and which preferentially, frequent background of was responsible for the tuberculosis which our patient had also had in death of the patient, merits discussion. The the past. primary pathogenetic mechanism that we http://jnnp.bmj.com/ con- Gajdusek et al'19 published a provocative report, sidered in our patient was some kind of infection, wherein a or an neurosurgeon with clear cutaneous immunological reaction to infection, or manifestations of Kohlmeier-Degos disease died both. With no inflammatory cells in or around of the typical neurological and neuropathological any of the several blood vessels encountered in of the manifestations Jacob-Creutzfeldt's disease. An leptomeninges and CNS parenchyma, an injection of his brain extract produced the latter infective aetiology was hard to support. Of the disease in a chimpanzee and a squirrel monkey. 10 published cases only that of Howard and et Gajdusek al suggested that the on September 26, 2021 by Nishida"5 appears to have had viral aetiology, aetiologic agent as of these two disorders might be the same or suggested from the presence of virion-like particles virus, that malignant activated a on electronmicroscopy, in the degenerating endo- atrophic papulosis thelial cells of the pre-existing Jacob-Creutzfeldt's infection. cutaneous blood vessels. In As the neuropathological in our only two other cases, those of McFarland et al12 process patient was characterised by the virtual absence of any and Gever et al,6 was there a preceding infection and with herpes zoster virus inflammatory reaction, as there was extensive and the presence in the presence of fibrin thrombi and fibrinous exuda- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.2.156 on 1 February 1981. Downloaded from

160 Darab K Dastur, B S Singhal, and H J Shroff tion, a disorder in clotting mechanism was with atrophy (Degos): Fatal cutaneo-intestinal considered. Roegnik and Farmer20 found increased syndrome. Arch Dermatol 1960; 81:181-8. increased serum fibrinogen levels in two of their 6 Gever SG, Freeman RG, Knox JM. Degos' three patients, and suggested that fibrinogen is disease (Papulosis Atrophicans Maligna): Report converted to a in the of a case with degenerative disease of the central "cryo-profibrin" presence of nervous system. South Med J 1962; 55:56-60. thrombin at cold temperatures. They also reported 7 Culicchia CF, Gol A, Erickson EE. Diffuse increased fibrinogen levels in patients with involvement in papulosis systemic erythematous (SLE) with renal atrophicans maligna. Neurol (Minneap) 1962; lesions. Increased fibrinogen levels might be a 12:503-9. nonspecific finding initiated by the clotting 8 Winkelmann RK, Howard FM, Perry HO, Miller mechanism itself, and arterial thrombosis can be RH. Malignant papulosis of skin and cerebrum: accompanied by increased, decreased or normal A syndrome of vascular thrombosis. Arch Der- fibrinogen levels. It appeared that we were deal- matol 1963; 87:94-102. 9 Vanderhaeghen JJ, Joffroy A, Achten G, War- ing with a "consumptive coagulopathy" in our szanski M, Reynaers H. Lesions vasculaires dans patient, as. evidenced by (1) a fall in the platelet la papulose atrophiante maligne de Degos. Quoted count in the second blood sample (collected two by Degos and Kalis.14 days before death), (2) an increase in plasma 10 Hall-Smith P. Malignant atrophic papulosis prothrobin time, (3) a rise in the activated partial (Degos' disease): Two cases occurring in the same thromboplastin time, and (4) a fall in circulating family. Br J Dermatol 1969; 81:817-22. haemoglobin level and packed-cell volume in 11 Horner FA, Myers GJ, Stumpf DA, et al. Ma- the second sample. The stimulus for the terminal lignant atrophic papulosis (Kohlmeier-Degos'

disease) in childhood. Neurol (Minneap) 1976; guest. Protected by copyright. abnormal clotting in and around the blood vessels 26:317-21. of the brain might have been some change in the 12 McFarland HR, Wood WG, Drowns BV, Meneses vessel wall of an inflammatory or immunological ACO. Papulosis atrophicans maligna (Kohlmeier- nature, or the presence of infection elsewhere in Degos disease): A disseminated occlusive vascu- the body. In our patient there was postmortem lopathy. Ann Neurol 1978; 3:388-92. evidence for the latter, in the form of severe 13 Besset A, Kurtz D, Bergoend H, Grosshans E, subacute pneumonitis and cystitis. Maleville J, Rohmer Fr. Papulose atrophiante maligne de Degos avec atteinte du systeme ner- We are indebted to the Department of Haema- veux central et presence d'anticorps anti-artere. Quoted by Degos and Kalis.14 tology of the JJ Hospitals for the blood reports of 14 Degos R, Kalis B. La papulose atrophiante mal- 1970; and to Dr Asha Veer, haematologist of igne. La Revue du Praticien 1969; 19:4335-41. Bombay Hospital, for her comments. Thanks are 15 Howard RO, Nishida S. A case of Degos' disease due to Ms N Patkar and Mr V Darekar, for the with electron microscopic findings. Trans Am histopathologic preparations, to Mr N Solanki for Acad Ophthalmol Otolaryngol 1969; 73:1097-112. the dark room work and to Ms Emma Alvares 16 Black MM, Hudson PM. Atrophic blanche lesions for the typing. (Degos' disease) in systemic lupus erythematosus. Br J Dermatol 1976; 95:649-52. References 17 Singhal BS, Dastur DK. Eales' disease with neuro- logical involvement. 1-Clinical features in 9

1 Kohlmeier W. Multiple Hautnekrosen bei throm- patients. J Neurol Sci 1976; 27:313-21. http://jnnp.bmj.com/ bangiitis obliterans. Arch Klin Exp Dermatol 18 Dastur, DK, Singhal BS. Eales' disease with 1941; 181:783-92. neurological involvement. 2. Pathology and 2 Degos R, Delort J, Tricot R. Dermatitie papulo- Pathegenesis. J Neurol Sci 1976; 27:323-45. squameuse atrophiante. Quoted by Degos and 19 Gajdusek DC, Gibbs CJ, Earle K, Dammin GJ, Kalis.14 Schoene WC, Tyler HR. Transmission of sub- 3 Degos R, Delort J, Tricot R. Papulose atrophi- acute spongiform encephalopathy to the chim- ante maligne (syndrome cutaneo-intestinal mor- panzee and squirrel monkey from a patient with tel). Quoted by Degos and Kalis.14 papulosis atrophicans maligna of Kohlmeier- 4 Strole WE, Clark WH, Isselbacher KJ. Pro- Degos. Proc X Int Congress of Neurology. A on September 26, 2021 by gressive arterial occlusive disease (Kohlmeier- Subirana, JM Burrows (eds). Amsterdam: Ex- Degos). A frequent fatal cutaneosystemic dis- cerpta Medica, 1977; 290-2. order. New Engl J Med 1967; 276:195-201. 20 Roenigk HH, Farmer RG. Degos' disease (malig- 5 Nomland R, Layton JM. Malignant papulosis nant papulosis). JAMA 1968; 206:1508-14.