Cerebral Atrophy
Short summary
A 52 year old began having difficulties with balance. His problems evolved and he had been seen by neurologists providing clinical evidence for a cerebellar motor syndrome. The most recent examination showed ataxia, dysarthria, nystagmus, dysphagia and hyperreflexia. Although the disease has progressed the patient is not severely disabled at this time.
Patient's questions
- Do you confirm the diagnosis?
- What do you think is the cause of this disease?
- Is there an effective medical treatment? Any alternative treatments?
- What do you think is the course and time frame of this pathology?
Medical Background
There is a history of deep venous thrombosis treated with Coumadin prior to the onset of these symptoms.
Medical opinion
The essential features of the case are that this gentleman who is now 55 years of age began having difficulties in probably mid-2007 primarily with balance. His problems have evolved and he has been seen by neurologists in 2008 and 2009 providing clinical evidence for a cerebellar motor syndrome. The examination from April 2009 is described as showing ataxia, dysarthria, nystagmus, dysphagia and hyperreflexia. The course has evolved over approximately three years and the patient is still ambulatory and able to engage in activities such as swimming, and therefore he is not severely disabled at this time. There is a history of deep venous thrombosis treated with Coumadin prior to the onset of these symptoms but there was no catastrophic onset and the disorder has progressed. Investigations that have been performed and that are negative according to the request for consultation include paraneoplastic antibodies, acetylcholine receptor antibodies, genes for spinocerebellar ataxia type 1, 2, and 3, Friedreich’s ataxia, ataxia with oculomotor apraxia, and the gene tests for hereditary spastic paraplegia including SPG 6 and 7. Neurophysiological tests have apparently not been informative. The patient has received a diagnosis of sporadic ataxia.
I am lead to believe from these notes that there is no family history of this disorder. There is no comment in the record of the possibility of consanguinity between the parents
FORMULATION AND DIFFERENTIAL DIAGNOSIS
The case therefore is one of sporadic ataxia and its differential diagnosis.
There is no suggestion here of ischemic or hemorrhagic cerebellar disease, nor a mass lesion within the cerebellum. I see no history of toxic exposures in the record, including excessive abuse of alcohol. There is nothing here to suggest an acute infection, and therefore the possibility of a post-infectious cerebellitis is unlikely, and the progressive course would also be unusual for that disorder. Creutzfeldt-Jakob disease can affect the cerebellum principally but the course has been relatively slow over three years. Paraneoplastic disorders have been specifically considered, but in the absence of systemic ill health and negative paraneoplastic antibodies this is less of a consideration. Nevertheless, if this continues to be a concern then it would be useful to obtain pan-CT scan of chest, abdomen and pelvis.
There are dominant ataxias including spinocerebellar ataxia type 6 and type 8 that may not be clinically manifesting in the patient’s parents, and therefore if the clinical scenario warrants then it may be necessary to obtain the remainder of the genetic tests for dominant disorders as well as for the recessive disorder ataxia ocular motor apraxia type 2. The patient is Italian therefore unlikely to be suffering from disorders such as those that affect the French-Canadian kindred, namely ARCA 1.
A central concern in this case is the possibility of Multiple System Atrophy, cerebellar type. I do not have any clear information from the record of urinary urge incontinence, although there is some suggestion of pressure on the bladder, and this may be referring to difficulty with urination. This would be an important clinical symptom. Similarly the presence of erectile dysfunction early in the course would be an important feature to inquire about, and there is nothing in the record about this. Sleep disturbance including rapid eye movement (REM) sleep behavior disorders are frequently seen in MSA-c and need to be inquired about specifically. Pathologic laughing and crying can occur in almost 35-40% of these patients and is worth a specific set of questions. I do not see a record of the blood pressure measurement lying and standing, and this is an essential feature of the evaluation to look for autonomic neuropathy manifesting as neurogenic orthostatic hypotension. The last brain MRI was performed in May 2009 and is reported as showing some cerebellar volume loss but there is no report of volume loss in the brainstem, and whereas one expects to see prominent pontine atrophy in MSA-c, this may not be present in the first few years of the illness and does not rule out this disorder.
In specific answer to the questions, it certainly seems that there is a cerebellar syndrome here, but there is no enough information at this point to
make a diagnosis of “sporadic ataxia”
I am lead to believe from these notes that there is no family history of this disorder. There is no comment in the record of the possibility of consanguinity between the parents
FORMULATION AND DIFFERENTIAL DIAGNOSIS
The case therefore is one of sporadic ataxia and its differential diagnosis.
There is no suggestion here of ischemic or hemorrhagic cerebellar disease, nor a mass lesion within the cerebellum. I see no history of toxic exposures in the record, including excessive abuse of alcohol. There is nothing here to suggest an acute infection, and therefore the possibility of a post-infectious cerebellitis is unlikely, and the progressive course would also be unusual for that disorder. Creutzfeldt-Jakob disease can affect the cerebellum principally but the course has been relatively slow over three years. Paraneoplastic disorders have been specifically considered, but in the absence of systemic ill health and negative paraneoplastic antibodies this is less of a consideration. Nevertheless, if this continues to be a concern then it would be useful to obtain pan-CT scan of chest, abdomen and pelvis.
There are dominant ataxias including spinocerebellar ataxia type 6 and type 8 that may not be clinically manifesting in the patient’s parents, and therefore if the clinical scenario warrants then it may be necessary to obtain the remainder of the genetic tests for dominant disorders as well as for the recessive disorder ataxia ocular motor apraxia type 2. The patient is Italian therefore unlikely to be suffering from disorders such as those that affect the French-Canadian kindred, namely ARCA 1.
A central concern in this case is the possibility of Multiple System Atrophy, cerebellar type. I do not have any clear information from the record of urinary urge incontinence, although there is some suggestion of pressure on the bladder, and this may be referring to difficulty with urination. This would be an important clinical symptom. Similarly the presence of erectile dysfunction early in the course would be an important feature to inquire about, and there is nothing in the record about this. Sleep disturbance including rapid eye movement (REM) sleep behavior disorders are frequently seen in MSA-c and need to be inquired about specifically. Pathologic laughing and crying can occur in almost 35-40% of these patients and is worth a specific set of questions. I do not see a record of the blood pressure measurement lying and standing, and this is an essential feature of the evaluation to look for autonomic neuropathy manifesting as neurogenic orthostatic hypotension. The last brain MRI was performed in May 2009 and is reported as showing some cerebellar volume loss but there is no report of volume loss in the brainstem, and whereas one expects to see prominent pontine atrophy in MSA-c, this may not be present in the first few years of the illness and does not rule out this disorder.
In specific answer to the questions, it certainly seems that there is a cerebellar syndrome here, but there is no enough information at this point to
make a diagnosis of “sporadic ataxia”
SUGGESTIONS FOR MANAGEMENT
Recommendations for management are to specifically inquire about urge incontinence, erectile dysfunction, REM sleep behavior disorder, and examine the patient supine and after two minutes of standing to look for a drop in the systolic blood pressure. A 30mm drop would provide a diagnosis of probable MSA-c, and a drop of 20mm would make this a “possible” rather than “probable” diagnosis. This is according to the consensus criteria for the MSA-c diagnosis (Gilman et al., 2008). A repeat brain MRI should be performed looking for progressive atrophy of the cerebellum and brainstem compared to the prior scan, and for the characteristic hot-cross-bun sign in the pons often seen in MSA. If in fact the patient does not have the autonomic dysfunctions of urge incontinence, erectile dysfunction, neurogenic hypotension, and REM sleep behavior disorder one may consider the need to actually continue with the genetic workup for the dominant and remaining sporadic ataxias; and gene tests should be sent off for this.
We are also seeing patients who have a mitochondrial basis to their ataxia although this patient is slightly old for that diagnostic category, and if in fact that is a possibility, then other blood tests would be required including pyruvate, lactate, serum amino acids, urine organic acids, carnitine, acetylcarnitine, and co-enzyme Q10 measurement in the blood. If all the rest of the workup is negative, and the MRI continues to show only cerebellar volume loss, then one can consider further investigations including muscle biopsy, but that is only to be undertaken after extensive workup in a center that specializes in cerebellar disorders
We are also seeing patients who have a mitochondrial basis to their ataxia although this patient is slightly old for that diagnostic category, and if in fact that is a possibility, then other blood tests would be required including pyruvate, lactate, serum amino acids, urine organic acids, carnitine, acetylcarnitine, and co-enzyme Q10 measurement in the blood. If all the rest of the workup is negative, and the MRI continues to show only cerebellar volume loss, then one can consider further investigations including muscle biopsy, but that is only to be undertaken after extensive workup in a center that specializes in cerebellar disorders
TREATMENT OPTIONS
With respect to medications I have had some success using Trihexyphenidyl for tremor, and medications such as amantadine, the serotonin reuptake inhibitors including Prozac, Zoloft, and celexa may be helpful both for improvement of speech, and also for elevation of mood that can be a problem in these disorders. Clonazepam can be helpful with spasticity and tremor as well as anxiety. If indeed this gentleman has MSA and he progresses to develop some symptoms of parkinsonism, then the dopaminergic agonists may be necessary later in his course. Medications for urinary urgency are available, and if there is postural hypotension then I have found pyridostigmine to be effective, as recently described (Singer et al., 2006), either alone or in conjunction with fludrocortisone and midodrine. The patient may benefit from the use of multivitamins, and co-enzyme Q10, although this is not proven to be effective. Finally, continued evaluation by physical therapy, occupational therapy and speech therapy will be helpful, and it is important to prevent aspiration, as this is a common cause of early demise in this patient population
PROGNOSIS
With respect to the course and timeframe of this disorder, this will be fully dependent upon the nature of the diagnosis. It is premature to comment on the prognosis without the diagnosis being established and for this reason I have made the recommendations as set out in this letter
