Acute-Onset Cerebellar Symptoms in Lhermitte–Duclos Disease: Case Report
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- Hariri, O.R., Khachekian, A., Muilli, D. et al. Cerebellum (2013) 12: 127. doi:10.1007/s12311-012-0394-2
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Adult-onset Lhermitte–Duclos disease (LD), or dysplastic cerebellar gangliocytoma, is a hamartoma considered pathognomonic for Cowden disease. Classically, LD has a progressive and insidious onset of symptoms. In this case report, we present a patient having rapid neurological deterioration from acute-onset LD. There are only three reported cases of acute LD presentation. A 22-year-old female presented to the emergency department with diplopia, dysarthria, dysphagia, and gait instability which developed within 6 h. A non-contrast CT scan revealed diffuse attenuation in the left cerebellum and mild ventricular dilatation. LP revealed no organisms. Magnetic resonance imaging revealed salient “tiger stripe” appearance of the left cerebellar cortex and effacement of the fourth ventricle. The patient subsequently underwent suboccipital craniotomy and gross total resection of the lesion. The tumor histology showed distortion of normal cerebellar architecture with dysplastic ganglion cells, loss of Purkinje cells, atrophy of the white matter, and expansion of cerebellar folia. Findings were consistent with adult-onset Lhermitte–Duclos disease.
KeywordsLhermitte-DuclosCowden diseaseDysplastic cerebellar gangliocytomaPTEN (Phosphatase and tensin homolog) mutation
Lhermitte–Duclos disease (LD), also known as dysplastic gangliocytoma of the cerebellum, is a World Health Organization grade I tumor first described by the French neurologists Jacques Lhermitte and P. Duclos in 1920 and named in their honor. LD is a slow-growing, progressive, nonmalignant tumor occurring exclusively in the unilateral cerebellum. It usually presents with progressive mass effect in the posterior fossa, leading to cerebellar dysfunction, non-communicating hydrocephalus, and signs of increased intracranial pressure .
Adult onset of LLD is considered to be a phenotypic variant of Cowden syndrome (CS) and can be the initial presenting symptom of CS, preceding the diagnosis in 40–70 % of cases ; however, LD may also occur as a sporadic isolated disease . If present, LD is considered pathognomonic for CS by the International Cowden Consortium Criteria. There is also a strong genetic association between LD and CS, causing the presence of concomitant malignancies that arise from cutaneous and neural ectoderm . Thus, surveillance for malignancies in patients with LD is extremely important.
The purpose of this case report is to increase awareness about LD by presenting a 22-year-old patient with an acute onset of LD. To this date, only less than ten reported cases of acute-onset LD have been reported [1, 5, 6]. To the best of the authors' knowledge, this is the first case reported within the USA of acute-onset cerebellar symptoms as the presenting sign of Lhermitte–Duclos disease.
A 22-year-old right-handed dominant Hispanic female presented to the emergency department with an abrupt onset of diplopia, dysarthria, dysphagia, and gait instability with a left-sided preference, all of which developed within a span of 6 hours. The patient described 3-day history of severe headaches accompanied by nuchal rigidity, photophobia, nausea, and vomiting upon awakening each morning.
Upon physical examination, the patient was awake, alert, and oriented to person, place, time, and event. Neurological exam was notable for mild left-sided horizontal gaze nystagmus, bilateral dysmetria, and dysdiadochokinesia with predominately left-sided findings, ataxia to the left, positive Rhomberg, and pronator drift on the left side. Her dysarthria was attributable to extremely slowed speech and inability to articulate. The remainder of the exam was unremarkable. A lumbar puncture was performed and revealed no organisms.
The patient was taken to the operating room and underwent a suboccipital craniectomy, with the goal of de-bulking the mass as much as possible, which eventually led to the total resection of the left cerebellar hemisphere. The postoperative course was unremarkable, and patient remained neurologically stable with a GCS of 15 and a normal mental status exam. She experienced significantly less vertigo, dysarthria, dysmetria, dysphagia, dysdiadochokinesia, and conjugate roving eye movements. The patient continued to be followed up in the neurosurgery and internal medicine outpatient clinics for development of signs or symptoms suggestive of Cowden syndrome.
Due to the association of LD with CS, she underwent a malignancy work-up, which initially included a CT of abdomen and pelvis, showing lymphadenopathy in bilateral iliac regions; however, a follow-up CT showed no evidence of malignancy. Due to her increased chances of developing cervical cancer, she also had her annual pap smear, which was found to have a low-grade squamous intraepithelial lesion with HPV changes, which was further worked up with a colposcopy. This showed benign fragments of endocervical glands and stroma that were negative for dysplaisa; however, a tiny focus of atypical metaplastic epithelium was present, which required a 6-month follow-up and a repeat pap smear. Unfortunately, she has not reported for her repeat pap smear at this point.
At the same time as this entire work-up was taking place, the patient complained of stiffness in bilateral feet, which was attributed to polyarthalgia with negative X-ray results. Although her skin examination showed no evidence of rash, a rheumatologic work-up was initiated, which revealed a positive ANA and positive antimicrosomal antibody, negative double-stranded DNA and negative anti-rho antibodies, but elevated ESR and CRP. She was referred to the rheumatology clinic and was diagnosed with rheumatoid arthritis and begun on therapy with instructions to follow-up in clinic. Unfortunately, she was not compliant with her follow-up appointments.
To the best of our knowledge, there is only one case report by Nair et al.  which shows a rapid neurological deterioration in a patient with Lhermitte–Duclos disease. However, in their case, there is a simultaneous existence of cerebellar LD with dysembryoplastic neuroepithelial tumor (DNET). Since DNET has a much greater proliferative potential in compression to the hamartomatous nature of LD, a rapid neurological deterioration can be expected. In our patient, the removed mass was purely consistent with dysplastic gangliocytoma of the cerebellum and no other aggregative proliferative pathology. However, the extension of dysplasia has produced enough mass effect to cause a compression on the peduncle and tegmentum, effacement of the fourth ventricle, and an acute increase in intracranial pressure secondary to obstructive hydrocephalus, which is apparent on MRI studies.
Cowden syndrome is the prototype of a group of germline mutations called phosphatase and tensin homolog (PTEN) hamartoma tumor syndromes (PHTS) . The mutation involves a germline tumor suppressor gene called PTEN, which manifest themselves phenotypically as PHTS. Recently, this genetic disorder has been attributed to the mutation of PTEN gene on chromosome 10q22-23 . This is an autosomal-dominant mutation affecting over 80 % of patients with CS . Among those with the mutation, phenotypic expression is 99 % by age 30 . Although PTEN mutation plays a role in diagnosis of patients with Cowden syndrome, its absence does not exclude Cowden syndrome .
The incidence of Cowden syndrome is thought to be approximately 1 in 20,000. It is diagnosed clinically based on the combination of criteria, which include pathognomonic, major, and minor. The International Cowden Consortium Criteria for the diagnosis of Cowden disease includes pathognomonic criteria for mucocutaneous lesions, two major criteria, one major and three minor criteria, or four minor criteria. Mucocutaneous lesions can include facial trichilemmomas, acral keratoses, papillomatous papules, or mucosal lesions. Major criteria include the presence of breast carcinoma, thyroid carcinoma, macrocephaly, Lhermitte–Duclos disease, or endometrial carcinoma. Minor criteria include other thyroid lesions, mental retardation, gastrointestinal hamartomas, fibrocystic disease of the breast, lipomas, fibromas, or genitourinary tumors . Our patient did not meet the criteria for Cowden disease; however, due to the diagnosis of Lhermitte–Duclos disease, surveillance for Cowden disease continued. According to Robinson et al., the diagnosis of either condition should prompt a search for the other since recognizing an association can lead to an early diagnosis of cancer . These malignancies are part of the spectrum of nodular DNETs that should be observed and monitored .
Our patient's diagnosis of Lhermitte–Duclos disease is a phenotypic variant of CS, which includes enlargement of folia caused by a thickened granular layer . This granular layer is due to cellular hypertrophy and increased myelination within the molecular layer . The internal granular layer is, in turn, replaced by hypertrophic ganglion cells, giving the entire layer its characteristic thickness—a feature of LD [4, 10]. Similarly, Purkinje cells are also either diminished or absent completely . These characteristic changes in the molecular layer give this disease the pathognomonic findings on imaging studies. Hypo/hyperintense signals seen on T1/T2 MRI sequences are derived from CSF in the sulci and the white matter. In a similar manner, an intermediate signal is derived from the cerebellar cortex . Finally, the central core of the T1 hypointensity and T2 hyperintensity corresponds to the thinned white matter, widened granular cell layer, and the inner portions of the dysplastic molecular layer .
The presence of dermatologic lesions should also raise the concern for the presence of Cowden syndrome in a patient with Lhermitte–Duclos Disease . Cowden syndrome has been qualified as one of the phakomatoses, which are a spectrum of syndromes with characteristic cutaneous and neurological manifestations . The cutaneous features of Cowden disease can alone serve as a diagnostic criterion; however, in our patient, we were not able to find any dermatologic manifestations. Instead, she had rheumatologic manifestations, which could have possibly been a systemic manifestation of an underlying genetic disorder.
Treatment of Lhermitte–Duclos disease involves a multidisciplinary approach, involving neurosurgeons, gynecologists, oncologists, and dermatologists. In patients with PTEN mutations, the lifetime risk of associated malignancies is increased since it is thought that cells harboring the mutant PTEN allele are predisposed to malignant transformation . Unfortunately, some of these mutations become insensitive to ubiquitously used chemotherapy regimens including cisplatin, thus restricting treatment options . According to a study published by Tan et al. in January 2012 in Clinical Cancer Research, estimated lifetime risks of breast, thyroid, endometrium, colorectal, renal cell carcinoma, and melanoma were 85.2, 35.2, 28.2, 9.0, 33.6, and 6 %, respectively . In regards to breast cancer, PTEN mutation is thought to be a promoter mutation, whereas the mutation associated with colorectal cancer is thought to be a nonsense mutation . Fortunately, majority of women (75 %) who carry the mutation for Cowden syndrome are diagnosed with benign carcinomas of the breast, including ductal hyperplasia, lobular atrophy, fibroadenomas, and fibrocystic changes . However, in the remaining 25 % of women, who are usually diagnosed premenopausally, cancers are ductal in origin with an increased incidence of bilateral multifocality .
Although our patient was lost to follow-up and consequently did not receive further evaluation for genetic defects, long-term surveillance for patients with Cowden syndrome who have the germline PTEN mutation is of particular importance. Current recommendations for screening these patients include semiannual clinical breast exams starting at age 20–25 years and annual mammogram or breast MRI starting at age 30 . In case of a positive family history, surveillance begins 5 years prior to the earliest diagnosis in the family member . In these patients, mastectomy may also be an appropriate risk-reducing step, similar to that performed in BRCA-positive hereditary breast and ovarian cancers . If the diagnosis occurs in females, yearly pap smears should also be undertaken with any abnormal results further investigated.
Lhermitte–Duclos disease is a variant of Cowden syndrome and has a strong genetic association with PTEN mutations. Cowden syndrome, in turn, is the prototype of PHTS. Patients with this autosomal-dominant germline mutation can present clinically with sudden onset of neurological signs and symptoms, with diagnosis becoming evident upon surgical evaluation and pathological examination. Since these patients have a predisposition for benign and malignant neoplasms involving the breast, thyroid, endometrium, cervix, colorectal, kidney, skin, and central nervous system, annual surveillance for early detection of malignant transformations in patients with LD is of utmost importance.
Conflict of Interest
In writing this manuscript, there was no conflict of interest. There were no personal or financial relationships that could have contributed in any way to the writing of this manuscript. No potential conflicts or biases exist.